Postepy Hig Med Dosw. (online), 2007; 61: 736-759
Review


Liver X receptors (LXRs). Part I: Structure, function, regulation of activity, and role in lipid metabolism
Receptory wątrobowe X (LXR). Część I: Budowa, funkcja, regulacja aktywności i znaczenie w metabolizmie lipidów
Grażyna Wójcicka1  , Anna Jamroz-Wiśniewska1  , Krzysztof Horoszewicz2  , Jerzy Bełtowski1  
1Department of Pathophysiology, Medical University, Lublin, Poland
2Department of Surgery, Regional Specialistic Hospital, Biała Podlaska, Poland
Corresponding author
Dr hab. n. med. Jerzy Bełtowski, Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland; e-mail: jerzy.beltowski@am.lublin.pl

Received:  2007.05.28
Accepted:  2007.11.05
Published:  2007.12.03

Streszczenie
Receptory wątrobowe X (LXR) typu a i b należą do rodziny receptorów jądrowych, które tworzą heterodimery z receptorem retinoidowym X i po związaniu ligandu pobudzają transkrypcję genów. Początkowo zostały opisane jako “receptory sieroce”, a następnie wykazano, że ich naturalnymi ligandami są utlenione pochodne cholesterolu (oksysterole). Otrzymano też kilka syntetycznych agonistów tych receptorów, takich jak T0901317 oraz GW3965. Oksysterole powstają w ilościach proporcjonalnych do zawartości cholesterolu w komórce, i dzięki temu receptory LXR działają jako “mierniki cholesterolu” chroniące przed jego nadmiarem poprzez: 1) hamowanie wchłaniania cholesterolu z przewodu pokarmowego, 2) stymulację usuwania cholesterolu z komórek do lipoprotein o wysokiej gęstości przez transportery wiążące ATP, ABCA1 i ABCG1, 3) pobudzanie przekształcania cholesterolu w kwasy żółciowe w wątrobie oraz 4) aktywację wydalania cholesterolu i kwasów żółciowych do żółci. Ponadto, agoniści LXR pobudzają syntezę kwasów tłuszczowych stymulując ekspresję lipogennego czynnika transkrypcyjnego, białka wiążącego element odpowiedzi na sterole typu 1c (SREBP-1c), co prowadzi do wzrostu stężenia trójglicerydów w osoczu oraz stłuszczenia wątroby. W pracy omówiono budowę i działanie receptorów LXR, ich endo- i egzogennych agonistów i antagonistów, regulację ekspresji i aktywności LXR oraz ich znaczenie w regulacji metabolizmu cholesterolu i lipidów. W towarzyszącym artykule opisano inne działania receptorów LXR, zmiany ekspresji tych receptorów oraz poziomu ich endogennych agonistów w warunkach patologicznych oraz implikacje terapeutyczne.
Słowa kluczowe: receptory wątrobowe X • oksysterole • zwrotny transport cholesterolu • lipogeneza • miażdżyca


Summary
Liver X receptors (LXRs) a and b belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor and, upon ligand binding, stimulate the expression of target genes. LXRs were initially described as orphan receptors and oxidized cholesterol derivatives (oxysterols) were later identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors which protect from cholesterol overload by: 1) inhibiting intestinal cholesterol absorption, 2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1, 3) activating the conversion of cholesterol to bile acids in the liver, and (4) activating biliary cholesterol and bile acid excretion. In addition, LXR agonists activate de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Here we describe the structure and function of the LXRs, their endo- and exogenous agonists and antagonists, the regulation of LXR expression and activity, and their role in the regulation of cholesterol and lipid metabolism. In the accompanying article we characterize other effects of LXRs, alterations in LXR expression, and changes in the level of their endogenous agonists in pathological conditions as well as therapeutic implications.
Key words: liver X receptor • oxysterols • reverse cholesterol transport • lipogenesis • atherosclerosis




Abbreviations:
9cRA9-cis retinoic acid; ACAT – acyl-CoA: cholesterol acyltransferase; ACC – acetyl-CoA carboxylase; CETP – cholesterol ester transfer protein; ChREBP – carbohydrate response element binding protein; CNRE – cyclic AMP response element and a negative response element; CTX – cerebrotendinous xanthomatosis; EL – endothelial lipase; FAS – fatty acid synthase; FF-MAS – follicular fluid meiosis-activating sterol; FXR – farnesoid X receptor; HDL – high-density lipoproteins; HPL – hepatic lipase; LCAT – lecithin: cholesterol acyltransferase; LDL – low-density lipoproteins; LPL – lipoprotein lipase; LXR – liver X receptor; LXRE – liver X receptor response element; PLTP – phospholipid transfer protein; PPAR – peroxisome proliferator-response element; ROS – reactive oxygen species; RXR – retinoid X receptors; SCD-1 – stearoyl-CoA desaturase-1; SREBP – sterol response element binding protein; T-MAS – testes meiosis-activating sterol; TR – thyroid hormone receptor; VDR – vitamin D receptor; VLDL – very-low-density lipoproteins.
1. INTRODUCTION
Liver X receptors (LXRs) belong to a large family of nuclear receptors which bind to the regulatory region of target genes and, upon ligand binding, stimulate their transcription. LXRs were initially isolated from a human liver cDNA library as an orphan receptor since its natural ligand was unknown [171]. Later, oxidized cholesterol derivatives or oxysterols were identified as specific ligands of LXRs, which are therefore also named “oxysterol receptors”. Studies performed during the last decade suggest that LXRs are “cholesterol sensors” which, in response to excess cholesterol, stimulate its transport to the liver and biliary excretion. In this review we summarize the current knowledge about the structure and function of LXRs, their endo- and exogenous ligands, the regulation of LXR expression and activity, and their role in cholesterol and lipid metabolism. In a related article we characterize other roles of LXRs, alterations of endogenous LXR signaling in pathological conditions, the therapeutic potential of LXR modulators, and the effect of currently used drugs on the LXR signaling system.
2. LIVER X RECEPTOR: AN OVERVIEW
There are two LXR isoforms in mammals, termed LXRa (NR1H3) and LXRb (NR1H2). LXRa is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRb is ubiquitously expressed at a lower level [7,136]. Both isoforms share almost 80% identity of their amino-acid sequences. The LXR molecule consists of four domains: 1) an N-terminal ligand-independent activation function domain (AF-1) which may stimulate transcription in the absence of a ligand, 2) a DNA-binding domain (DBD) containing two zinc fingers, 3) a hydrophobic ligand-binding domain (LBD) required for ligand binding and receptor dimerization (see below), and 4) a C-terminal ligand-dependent transactivation sequence, also referred to as activation function-2 (AF-2), which stimulates transcription in response to ligand binding.
LXRa exists in three variants originating from alternative promoter usage and mRNA splicing: LXRa1, LXRa2, and LXRa3. [36]. LXRa1 is the major variant in most tissues except the testis, where the LXRa2 predominates, whereas LXRa3 is expressed at low levels in the lung, thyroid gland, and spleen. All three variants bind DNA, but LXRa2 is less active in stimulating transcription than LXRa1, whereas LXRa3 is unable to bind ligands and fails to stimulate transcription; LXRa3 may in fact antagonize the function of the other isoforms.
Both LXRa and LXRb function as heterodimers with the retinoid X receptor (RXR), a common partner for several nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), vitamin D receptor (VDR), thyroid hormone receptor (TR), and farnesoid X receptor (FXR). LXR/RXR is a so-called “permissive heterodimer” which may be activated by either LXR agonist or 9-cis retinoic acid (9cRA), a specific RXR ligand. Simultaneous application of the agonists of both partners usually elicits a stronger response than either agonist alone. The LXR/RXR complex binds to a liver X receptor response element (LXRE) in the promoter region of target genes. The “ideal” LXRE sequence is a direct repeat-4 (DR-4) DNA fragment consisting of two AGGTCA hexameric half-sites separated by a 4-nucleotide spacer. However, analysis of functional LXRE in the known target genes revealed that the consensus sequences contain a number of invariant nucleotides in each half-site, but the nucleotides at other positions may vary considerably. Although LXRa and LXRb have similar affinities to the idealized LXRE, they may have different affinities to specific nonideal LXRE sequences in certain genes [45,73].
Interestingly, similarly to PPAR and FXR, LXRs may stimulate transcription to some extent even in the absence of a ligand. In contrast, VDR/RXR and TR/RXR heterodimers do not exhibit any ligand-independent stimulatory activity. However, LXRs may also actively repress the expression of some genes in the unliganded state [45]. Therefore, a “three-step” model has been proposed to describe the activation of LXRs (Figure 1). According to this model, in the absence of agonist, the LXR/RXR heterodimer actively inhibits transcription by recruiting nuclear co-repressors. Ligand binding first induces dissociation of the co-repressors, leading to moderate stimulation of transcription, and then elicits recruitment of co-activator( s), thus causing a maximal stimulation of transcription. This model explains why the expression of some target genes is higher in LXR-deficient mice than in wild-type animals, although it is of course unresponsive to stimulation by LXR agonists (Figure 1). At least two studies [90,103] have demonstrated that the LXR/RXR heterodimer may also nonspecifically bind to the FXR response element (FXRE).
Figure 1. Two models of the regulation of gene expression by the LXR/RXR heterodimer. Left: unliganded LXR/RXR actively suppresses transcription (1) by recruiting co-repressors (CoR). Agonist (Ag) binding induces dissociation of the co-repressor, which results in moderate stimulation of transcription (2), and later recruits co-activators (CoA), leading to maximal stimulation of transcription (3). Removal of active suppression by LXR knockout (4) causes moderately higher expression of a target gene compared with the wild-type phenotype. Right: unliganded LXR/RXR heterodimer moderately stimulates transcription because co-repressors are not bound (1). Agonist binding induces a maximal stimulation of transcription by recruiting co-activators (2). In the absence of LXR, transcription is minimal (3) because the baseline stimulatory eff ect of unliganded LXR is removed. Vertical black bars qualitatively represent the level of gene expression. Various genes may be regulated according to the 1st or the 2nd model

LXR ligands may also inhibit the transcription of certain genes through several mechanisms, including: 1) stimulation of an intermediate regulatory protein which inhibits transcription or destabilizes mRNA, 2) binding of LXRs to other transcription factors and inhibiting their activity, 3) competition between LXRs and other transcription factors for a common pool of RXR, 4) competition between LXR/RXR heterodimers and other transcription factors for the same coactivators, and 5) binding of the LXR/RXR heterodimer to the LXRE sequence overlapping with the response element for other nuclear receptors.
Recently, an interesting novel mechanism through which LXRs may regulate gene expression was described [157,158]. Namely, in renal juxtaglomerular apparatus, cyclic AMP increases renin gene expression through an LXRa-dependent mechanism by stimulating the binding of LXRa to a specific DNA sequence referred to as “cyclic AMP response element and a negative response element” (CNRE) within a promoter region of the renin gene. This effect is not mimicked by classic LXR or RXR agonists and, vice versa, cAMP does not induce LXR binding to LXRE. Subsequently, Anderson et al. [4] have shown that apart from renin, many other genes may also be regulated in this manner.
3. OXYSTEROLS AS THE NATURAL LXR LIGANDS
3.1. Definition, classification, and origin of oxysterols
It is widely accepted that the major physiological LXR ligands are some monooxygenated derivatives of cholesterol referred to as oxysterols [70,92]. LXRs thus belong to a family of nonhormone nuclear receptors which, similarly to PPAR or FXR, are activated by metabolic intermediates normally found in the biological milieu at relatively high concentrations. Indeed, the EC50 value of LXRs for most oxysterols is within the low micromolar range, which is close to the normal levels of these compounds in plasma and tissues. The metabolic fate of oxysterols is faster than that of cholesterol and, therefore, their concentration better reflects short-term changes in cholesterol balance, which makes oxysterols good candidates for regulatory molecules. Although cholesterol has no measurable affinity to LXRs, some authors question the regulatory role of oxysterols, arguing that they are always present together with a 105–106 excess of cholesterol [13]. It should be noted that oxysterols also have other effects unrelated to LXR stimulation. For example, certain oxysterols inhibit the processing of sterol regulatory element-binding proteins (SREBPs) and thus inhibit cholesterol biosynthesis more efficiently than cholesterol itself.
There are three sources of oxysterols in the animal body:
• Endogenous production in enzymatic reactions.
• Endogenous production through the non-enzymatic reactive oxygen species (ROS)-dependent oxidation of cholesterol.
Delivery from alimentary sources.
In general, oxysterols produced in enzymatic reactions (Figure 2) are potent LXR agonists, whereas nonenzymatically generated ones have weak or no agonistic activity. Interestingly, natural oxysterol enantiomers have much higher affinity to LXRs than stereoisomers which are not endogenously generated [70].
Figure 2. Endogenous sterol LXR agonists. FF-MAS – follicular fluid meiosis-activating sterol, T-MAS – testes meiosis-activating sterol

Enzymatically generated oxysterols which are recognized by LXR ligands may be divided into three groups:
• Intermediates of the cholesterol biosynthetic pathway; until now 24(S),25-epoxycholesterol is the only representative of this group (Figure 2 and 3).
• Intermediary compounds in the synthesis of steroid hormones from cholesterol, i.e. 22(R)-hydroxycholesterol and, to a lesser extent, 20(S)-hydroxycholesterol (Figure 2 and 4).
• Several hydroxysterol compounds formed from cholesterol by “sterol hydroxylases”, many of them being various isoforms of cytochrome P450 (CYP).
Figure 3. Cholesterol biosynthetic pathway. Recognized LXR agonists are presented on the gray background. Geranylgeranyl-pyrophosphate, an LXR antagonist, is presented in the white frame. It should be noted that many intermediates in the synthesis of 24(S),25-epoxycholesterol from 24(S),25-epoxylanosterol have not been tested in the context of LXR agonism so far. Only enzymes relevant to this review are presented. HMGCR – 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34), SQS – squalene synthase (EC 2.5.1.21), SQE – squalene epoxidase (EC 1.14.99.7), OSC – oxidosqualene: lanosterol cyclase (EC 5.4.99.7), DHCR24-3b-hydroxysterol D24-reductase (desmosterol reductase, EC 1.3.1.72), CYP51 – lanosterol 14a-demethylase (sterol 14-demethylase, EC 1.14.13.70), DHCR14 – sterol 14a-reductase (EC 1.3.1.70), DHCR7–7-dehydrocholesterol reductase (EC 1.3.1.21)

Figure 4. Initial steps of steroidogenesis

3.2. 24(S),25-epoxycholesterol (24(S),25-EC)
24(S),25-EC is a potent LXR agonist with an EC50 of about 300 nM [70]. It is synthesized from dioxidosqualene in the shunt pathway of the mevalonate cascade (Figure 3) and is detected in high amounts in the liver and, to a lesser extent, in many other tissues [15]. In contrast to many oxysterols mentioned below, 24(S),25-EC is unlikely to be increased, but is rather reduced by cholesterol overload, since cholesterol reduces the expression and/or activity of several enzymes localized proximally to 24(S),25-EC in the mevalonate cascade.
3.3. Intermediates of steroidogenesis (Figure 4)
The conversion of cholesterol to pregnenolone is a first and rate-limiting step in steroidogenesis, i.e. the formation of steroid hormones from cholesterol. This reaction is catalyzed by CYP11A1, also referred to as “cytochrome P450 side-chain cleavage enzyme (P450scc)” or “cholesterol desmolase”, an enzyme contained in the inner mitochondrial membrane of steroidogenic tissues, including the adrenal cortex, ovaries, testes, and placenta. CYP11A1 is also detected at low levels in the nervous system, heart, pancreas, and skin [127]. This enzyme catalyzes three consecutive reactions leading to the conversion of cholesterol to pregnenolone with 22(R)-hydroxycholesterol (22(R)-HC) and 20,22-dihydroxycholesterol as intermediates (Figure 4), both of them being potent LXR activators. The monohydroxylated 20(S)-hydroxycholesterol is also an LXR agonist, but this compound is not endogenously generated. In contrast, pregnenolone as well as unnatural enantiomers, i.e. 22(S)-HC and 20(R)-HC, are inactive; in fact, 22(S)- HC has been reported to be an LXR antagonist [70].
3.4. Cholesterol hydroxylases and hydroxylated cholesterol derivatives
3.4.1. 24(S)-hydroxycholesterol
The family of hydroxylated cholesterol derivatives known to activate LXRs includes 24(S)-hydroxycholesterol (24(S)- HC), 25-hydroxycholesterol (25-HC), and 27-hydroxycholesterol (27-HC) (Figure 2 and 5). 24(S)-hydroxycholesterol, also referred to as “cerebrosterol”, is the most abundant hydroxysterol in the brain [96]. It is synthesized in neurons, but not in glial cells, by a cytochrome P450 CYP46 isoform (cholesterol 24-hydroxylase) [102]. 24(S)-hydroxycholesterol plays an important role in brain cholesterol homeostasis. Because cholesterol does not cross the bloodbrain barrier, it cannot be removed from this organ through the classical reverse-transport mechanism involving highdensity highdensity lipoproteins (HDLs). In contrast, 24(S)-HC crosses the blood-brain barrier and thus the conversion of cholesterol to 24(S)-HC is a main route of cholesterol efflux from the brain [17]. 24(S)-HC is detected in the blood at a concentration proportional to the brain weight/body weight ratio and is then taken up by the liver and further metabolized. In the liver, 24(S)-HC is excreted into the bile as sulfated or glucuronidated conjugates or is first converted to 7a,24(S)-dihydroxycholesterol by microsomal 24-hydroxycholesterol 7a-hydroxylase (CYP39A1) or by cholesterol 7a-hydroxylase (CYP7A1) and then further oxidized to bile acids [95,120]. The plasma concentration of 24(S)-HC reflects the balance between cerebral production and hepatic metabolism [21]. Due to the high relative brain weight, plasma 24(S)-HC is highest during the first year of life and then declines by a factor of four during the first two decades [21]. 24(S)-HC may be a relevant LXR activator in the brain since its concentration in this organ is about 100 µM, in contrast to only about 0.15 µM in plasma. Interestingly, the distribution of CYP46A1 closely resembles that of LXR in the brain [17]. In addition, CYP46A1 is expressed only in neurons, but not in glial cells. It was proposed that 24(S)-HC derived from neurons stimulates the efflux of cholesterol from glial cells to extracellular lipid-free apolipoprotein E by stimulating ABCA1 in an LXR-dependent manner (see below). This extracellular cholesterol may then be taken up by neurons and converted to 24(S)-HC [12]. Thus, feed-forward cross-talk between neurons and glial cells may link these two pathways of cholesterol removal from brain cells. Knockout of the CYP46A1 gene in mice results in a feedback suppression of cholesterol biosynthesis in the brain [83].
Figure 5. Synthesis and major metabolic pathways of cholesterol-derived oxysterols. CYP – cytochrome P450, Ch25-OHlase – cholesterol 25-hydroxylase not belonging to the CYP family

3.4.2. 27-hydroxycholesterol and cholestenoic acid
27-hydroxycholesterol (27-HC) is generated by the mitochondrial cholesterol 27-hydroxylase (CYP27) expressed in the liver and other cell types, including macrophages, fibroblasts, and endothelial cells. CYP27 is unique among other cytochrome P450 isoforms in that it catalyzes three consecutive oxidation reactions of a C-27 methyl group to alcohol (27-hydroxycholesterol), aldehyde, and carboxylic acid (3bâ-hydroxy-5-cholestenoic acid) [14] (Figure 6). However, the product dissociates from the enzyme after each step and has to compete with cholesterol for its active center to be further oxidized. Therefore, when the cholesterol concentration is high, little 27-HC is further oxidized to cholestenoic acid.
Figure 6. Synthesis of 27-hydroxycholesterol and cholestenoic acid by CYP27A1

In the liver, CYP27 is a first enzyme of a so-called alternative or acidic pathway of bile-acid synthesis, which accounts for the formation of about 4% of the bile-acid pool synthesized in humans [98]. In other cells, 27-HC is not only the LXR ligand, but may also be involved in cholesterol efflux, since both 27-HC and cholestenoic acid are removed from the cells in an HDL-independent manner. Up to 50% of cholesterol may be removed as 27-HC or cholestenoic acid from cultured cells [14]. This mechanism may be especially important in cells which have no direct contact with plasma and are thus relatively isolated from HDLs. Thus the conversion of cholesterol to 27-HC in peripheral tissues plays a role analogous to its conversion to 24(S)-HC in the brain. The amount of 27-HC formed in the cell is proportional to the cholesterol content and is markedly increased in fibroblasts and macrophages loaded with low-density lipoproteins [8,51]. Inhibition of CYP27 activity in cultured human macrophages induces a marked cholesterol accumulation [98]. These data confirm an important role of CYP27 in cholesterol efflux. Deficiency of CYP27 causes cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive disease characterized by dementia, ataxia, cataract, and multiple xanthomas in the brain and tendinous system. CTX is associated with premature atherosclerosis and increased cholesterol content in the vascular wall despite apparently normal plasma lipid profile [164].
Apart from being oxidized to cholestenoic acid, 27-hydroxycholesterol may be hydroxylated to 7a,27-dihydroxycholesterol by hepatic microsomal oxysterol 7a-hydroxylase (CYP7B1), distinct from cholesterol 7a-hydroxylase (CYP7A1). 7a,27-dihydroxycholesterol is further metabolized to chemodeoxycholic acid. Thus, 27-HC of peripheral origin may be a substrate for hepatic bile-acid production [10].
Cholestenoic acid is an even more potent LXR activator than 27-HC, with an EC50 of 200 nM, whereas its physiological concentration in plasma is 3–5 µM [151]. Most of the cholestenoic acid detected in plasma originates from the lung. Its concentration is reduced by 50% in patients after pulmonectomy and it also decreases in patients with obstructive or parenchymal lung diseases [9]. Most cells contain much more 27-HC than cholestenoic acid, whereas the amount of cholestenoic acid exceeds that of 27-HC in the culture medium because cholestenoic acid is more efficiently removed from the cell due to its greater water solubility [10].
3.4.3. 25-hydroxycholesterol
25-hydroxycholesterol (25-HC) is a minor oxysterol formed by a specific microsomal enzyme not belonging to the CYP family, cholesterol 25-hydroxylase, which contains two nonheme iron atoms [99]. 25-HC is then taken up by the liver, hydroxylated to 7a,25-dihydroxycholesterol by CYP7B1, and further metabolized to bile acids (Figure 5).
3.4.4. 4b-hydroxycholesterol
4b-hydroxycholesterol (4b-HC) is formed in the liver and possibly in the small intestine by CYP3A4 and is one of the major circulating oxysterols [19]. Interestingly, both the formation and the metabolism of this compound are extremely slow and its half-life is close to 50 hours. Indeed, although 4b-HC is converted in the liver to bile acids, this occurs at a very slow rate since all CYP isoforms studied to date have very weak activity toward this compound [18]. The plasma concentration of 4b-HC is about 70 nM, i.e. almost fivefold more than the concentration of 4a-HC, which is a product of nonenzymatic cholesterol autooxidation [19].
3.4.5. 7a-hydroxycholesterol
Cholesterol 7a-hydroxylase (CYP7A1) is a rate-limiting enzyme in the classical pathway of bile-acid synthesis in the liver. Indeed, most plasma 7a-cholesterol originates from a hepatic CYP7A1-catalyzed reaction. However, 7a-hydroxycholesterol is a weak LXR agonist, whereas its derivatives, cholic and chemodeoxycholic acids, are completely inactive [69].
3.5. Nonenzymatic sources of oxysterols
Various oxysterols are generated in ROS-mediated reactions; however, most of them have only weak, if any, LXR agonistic activity. These oxysterols are normally detected in plasma and tissues at concentrations much lower than those of enzymatic products. However, their concentration increases in pathological conditions associated with oxidative stress, and they may exert many unfavorable effects, such as inhibition of endothelium-dependent vasorelaxation [81], protein ubiquitination [108], endoplasmic reticulum stress [125], and apoptosis [91]. It is suggested that oxysterols may contribute to the pathogenesis of oxidative stress-related diseases such as atherosclerosis, together with other lipid peroxidation products [16,22,148]. For example, certain oxysterols such as 7-keto-, 7a-hydroxy-, 7b-hydroxy-, 5,6-epoxycholesterol, and 3b,5a,6b-trihydroxycholestane are detected in oxidized low-density lipoproteins [32] and in human atherosclerotic lesions [28]. The plasma concentration of 7b-hydroxycholesterol correlates with the carotid artery intima-media thickness, a marker of subclinical atherosclerosis [140], and is reduced by antioxidant treatment [131].
Finally, oxysterols are present in certain foods, usually constituting up to 1% of dietary cholesterol. The major diet-derived oxysterols include 7-ketocholesterol, 7a- and 7b-hydroxycholesterol, 5a,6a-epoxycholesterol (a-EPOX), 5b,6b-epoxycholesterol (b-EPOX), and cholestan 3\b,5,6b-triol (aTRIOL). They originate most likely from the ROS-driven oxidation of cholesterol during food preparation and storage. Indeed, oxysterols are contained mainly in cholesterol-rich food, in particularly high amounts in food stored for prolonged periods of time or processed at a high temperature in the presence of oxygen, such as dried milk powder, cheese, etc. Alimentary oxysterols are absorbed in the small intestine and incorporated into chylomicrons. However, oxysterols of alimentary origin do not bind to LXRs with high affinity [69].
3.6. Oxysterols in plasma
The total concentration of oxysterols in the plasma of healthy humans is about 1 µM, which is about 0.02% of cholesterol. This level may increase to up to 20–30 µM (0.5–0.75% of total cholesterol) in various disease states. The most available oxysterol in the blood is 27-HC (0.4 µM), followed by 24(S)-HC (0.15 µM), 7a-HC (0.1 µM), and 4bâ- HC (70 nM) [22]. Less available are bEPOX, a-TRIOL, and 7-KC (about 50 nM), whereas the concentrations of a-EPOX, 7b-HC, and 25-HC are only about 5 nM. Thus, enzymatically generated oxysterols (with the exception of 25-HC) circulate at higher amounts than nonenzymatically formed ones. The concentrations of nonenzymatically formed oxysterols may even be overestimated due to the rapid ex vivo oxidation of cholesterol during sample processing. Although oxysterols are slightly more hydrophilic than cholesterol itself, they circulate in plasma lipoproteins, and their distribution between lipoprotein fractions closely resembles that of cholesterol. The exception is cholestenoic acid, which is mostly detected in the water phase.
3.7. Oxysterols as LXR agonists
The precise order of potency of various oxysterols as LXR activators differs in various studies. However, it seems that the hydroxyl group in the side chain of the cholesterol molecule as well as cholesterol’s 3bâ-hydroxyl group are essential for LXR activation. Sterols with a 3a hydroxyl group are inactive. In most studies, 22(R)-HC, 20(S)-HC, and 24(S)-HC are the most potent agonists, whereas 25-HC and 27-HC have relatively weak activity [69,70]. Triple-knockout mice lacking CYP46, CYP27, and cholesterol 25-hydroxylase exhibit an impaired response of hepatic LXR target genes to dietary cholesterol load, which confirms an essential role of endogenous oxysterols in LXR signaling [37].
Most oxysterols have similar affinity toward LXRa and LXRb. In contrast, oxidation of the B ring of the cholesterol moiety to form, for example, 5,6-24(S),25-diepoxycholesterol leads to the generation of more specific LXRa agonists [69]. In addition, 6a-hydroxy bile acids have higher affinity to LXRa than to LXRb [150]. Two 6a-hydroxy bile acids, hyodeoxycholic acid (HDCA) and hyocholic acid (HCA), are synthesized by CYP3A4 from litocholic and chemodeoxycholic acids, respectively, and are detected in the liver at a concentration of about 30 µM. HDCA and HCA bind to LXRa with EC50 of 55 µM and 17 µM, respectively, which are close to or within the physiological range. Thus, HDCA and HCA are physiological LXRa-selective agonists, at least in the liver.
4. NON-OXYSTEROL LXR LIGANDS
4.1. Intermediates of cholesterol biosynthesis
Recently, Yang et al. [176] demonstrated that desmosterol (24-dehydrocholesterol), one of the intermediates in cholesterol biosynthesis, is a potent activator of LXRs (EC50=1 µM). In contrast, several other intermediates, such as lathosterol, lanosterol, and 7-dehydrocholesterol, are inactive (Figure 3). Inhibition of desmosterol reductase by triparamol leads to the up-regulation of LXR target genes due to the accumulation of endogenous desmosterol [176].
Janowski et al. [70] demonstrated that LXRa is activated by 4,4-dimethyl-5a-cholesta-8,14,24-trien-3b-ol, also referred to as follicular fluid meiosis-activating sterol (FF-MAS). FF-MAS was first isolated from preovulatory follicular fluid and stimulates meiosis of mammalian oocytes [25]. FF-MAS is an intermediate in cholesterol biosynthesis, which is produced from lanosterol by lanosterol 14a-demethylase (CYP51), and in most cells is rapidly converted to 4,4-dimethyl-5a-cholesta-8,24-dien-3b-ol (T-MAS) by sterol 14a-reductase (Figure 3). T-MAS (testis meiosis-activating sterol) was isolated from bull testis. In most tissues, including hepatocytes, where the cholesterol synthesis pathway is highly active, the levels of FF-MAS and T-MAS are below the detection limit since the latter is immediately converted to zymosterol. Due to low expression of the respective downstream enzymes, FF-MAS and T-MAS accumulate at high concentrations in the ovaries and testes, respectively (Figure 3). The affinity of FF-MAS and TMAS to LXR is relatively low and these compounds most likely also possess LXR-independent activities. In addition, LXR-activating oxysterols have no effect on meiosis. Nevertheless, abnormalities of gonadal function in mice lacking LXRs suggest that FF-MAS/T-MAS-LXR signaling may be important for gonadal function.
4.2. Glucose
Mitro et al. [112] recently demonstrated that glucose and glucose-6-phosphate bind to and activate LXRa and LXRb with EC50 of 300 µM and 3 µM, respectively. In contrast, other simple carbohydrates have no effect. In addition, feeding mice with glucose results in the up-regulation of LXR target genes in the liver and intestine. These data suggest that glucose is a physiological ligand of LXR, which thus may function not only as cholesterol, but also as a glucose sensor.
4.3. Synthetic and natural exogenous LXR ligands
Two nonsteroid synthetic LXR agonists, T0901317 and GW3965 (Figure 7), are commonly used in experimental studies. T0901317 activates both LXRa and LXRb with an EC50 of about 20 nM [142]. GW3965 has a greater affinity toward LXRb (EC50=30 nM) than LXRa (EC50=190 nM); however, the difference is too small to be useful in differentiating the two isoforms. T0901317 is not a completely selective LXR agonist since it activates also the pregnane X receptor (PXR) [145] and farnesoid X receptor [63]. The affinity of T0901317 for PXR and FXR is, however, much lower than for LXR (EC50=4–7 µM).
Figure 7. Most commonly used synthetic LXR agonists

Other synthetic LXR agonists are used occasionally. Acetylpodocarpic dimer (APD) is a derivative of podocarpic acid, which was isolated from the resin of a plant, Podocarpus [147]. APD activates LXRa and LXRb in the low nanomolar range [153]. An indole alkaloid, paxilline, produced by a fungus, Penicillium paxilli, is the first natural nonoxysterol LXR agonist. Its affinity for LXR is similar to that of 22(R)-HC. However, paxilline is unsuitable for in vivo studies due to its toxicity. In addition, it is not LXR-specific since it is also an antagonist of the large-conductance Ca2+-activated potassium channel [20]. Riccardin C is a natural nonsteroid compound isolated from liverworts which is an LXRa agonist and LXRb antagonist [156]. The search for compounds with specific agonistic and antagonistic activities toward both LXR isoforms is essential for future research in this field.
Interestingly, the hepatitis C virus core protein facilitates LXR/RXR binding to the LXRE. Due to the potent lipogenic effect of LXR, it is suggested that this mechanism may contribute to the liver steatosis frequently observed in patients chronically infected with HCV [115].
Plant cells do not synthesize cholesterol but several other sterols with similar chemical structure, such as sitosterol, stigmasterol, campesterol, brasicasterol, and ergosterol. Plant sterols are poorly absorbed from the intestine and inhibit cholesterol absorption by displacing it from bile micelles. Supplementation of plant sterols may reduce plasma cholesterol level and is considered a potential antiatherosclerotic therapy [124]. It has been demonstrated that stigmasterol, but not sitosterol, is a potent LXR ligand due to the double bond between C22 and C23 in the side chain of its sterol moiety [177]. In contrast, Plat et al. [128] observed that both sitosterol and campesterol effectively stimulated LXR in cultured intestinal Caco-2 cells. Kaneko et al. [75] have shown that certain oxidized derivatives of phytosterols (“oxyphytosterols”) are more effective LXR activators than 24(S),25-epoxycholesterol. Thus at least some exogenous phytosterols or their derivatives may be physiologically important LXR ligands.
4.4. Are all LXR agonists equivalent?
In most experimental systems, natural LXR ligands are less potent then synthetic agonists, which is usually interpreted as the result of the rapid metabolism of oxysterols to the inactive compounds. However, Albers et al. [2] recently demonstrated that 22(R)-HC is a partial agonist, i.e. it increases the affinity of LXR to both transcription co-activators and co-repressors, whereas T0901317 is a full agonist, i.e. it induces dissociation of co-repressors and binding of co-activators. The final effect of a given agonist depends on the relative availability of certain co-activators and co-repressors in a given cell and may thus be tissue and even gene specific [2].
4.5. LXR antagonists
Geranylgeranylpyrophosphate (GGPP), one of the products of the mevalonate cascade, inhibits the transcriptional activity of LXRa and LXRb by antagonizing their interaction with nuclear co-activators [50,53]. In contrast, geranylpyrophosphate, farnesylpyrophosphate, and mevalonate have no effect on LXR. Polyunsaturated fatty acids (PUFAs) of the n-3 and n-6 family, such as arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and linoleic acid, are competitive antagonists of the interaction between LXRs and their ligands [122,180]. In contrast, saturated fatty acids possess no, and monounsaturated fatty acids have only minimal, antagonistic activity. There is no difference between the antagonistic potencies of n-3 and n- 6 PUFAs, and the degree of unsaturation rather than spatial distribution of the double bonds seems to be the most important factor [179].
Song et al. [149] demonstrated that oxidized cholesterol sulfonate, 5a,6a-epoxycholesterol-3-sulfonate, normally detected in human plasma, inhibits the transcriptional activity of LXR. Interestingly, its enantiomer, 5b,6b-epoxycholesterol- 3-sulfonate, is not an LXR antagonist. 7-ketocholesterol- 3-sulfonate inhibits LXR with a potency similar to 5a,6a-epoxycholesterol-3-sulfonate. 5a,6a-epoxycholesterol- 3-sulfonate is most likely a product of the autooxidation of cholesterol-3-sulfonate, the most abundant sulfonated sterol in plasma and tissues, or it originates by the sulfonation of 5a,6a-epoxycholesterol by cholesterol sulfotransferase. Overexpression of cholesterol sulfotransferase inactivates LXR signaling and reduces the expression of LXR target genes both in vitro and in vivo [38]. These data suggest that the relative abundance of oxysterols and their 3-sulfonates, determined by the activities of cholesterol sulfotransferase and sulfatase, may be important in the regulation of LXR signaling (Figure 8). Currently it is not clear if sulfonated derivatives of enzymatically formed oxysterols are present in tissues and if they are also LXR antagonists.
Figure 8. Metabolic pathways of cholesterol-3-sulfonate and 5,6-epoxycholesterol-3-sulfonate. CST – cholesterol sulfotransferase, STS – sterol sulfatase, ROS – reactive oxygen species

5. REGULATION OF LXR EXPRESSION AND ACTIVITY
5.1. Regulation of LXR expression
Apart from agonists and antagonists, LXR signaling may be modulated by changes in receptor expression (Table 1). Several studies have shown that stimulation of the peroxisome proliferator activated receptors a and g (PPARa and PPARg) increases LXR expression. Tobin et al. [159] have shown that the PPARa agonists Wy14643 and gemfibrozil as well as the PPARg agonist rosiglitazone increase LXRa mRNA and protein levels in the rat liver. In vitro, PPARa agonists increase LXRa expression in isolated rat hepatocytes through the peroxisome proliferator response element (PPRE) contained in the 5’-flanking region of the LXRa gene [159]. The human LXRa gene also contains PPRE [88], and four-month administration of fenofibrate resulted in the up-regulation of LXRa in the peripheral blood monocytes of patients with type 2 diabetes [49]. Because fatty acids are endogenous PPARa agonists, they may also increase LXRa expression. Indeed, high-fat diet or fasting, both associated with elevation of the plasma fatty acid level, up-regulated hepatic LXRa in the rat [159]. Various saturated and unsaturated fatty acids increased LXRa expression also in cultured rat hepatoma cells in vitro [159]. Thus, whereas in the short run unsaturated fatty acids are LXR antagonists, long-term elevation of their level results in the up-regulation of LXRa gene expression.
Table 1. Regulation of LXR signaling

Chineti et al. [40] demonstrated that PPARa and PPARg agonists increase the expression of LXRa, but not of LXRb, in primary human and murine macrophages. In contrast, Chawla et al. [33] observed that only PPARg, but not PPARa, agonists increase LXRa gene expression in cultured human THP-1 macrophages. The PPARg agonist rosiglitazone increased the level of LXRa mRNA in cultured 3T3-L1 adipocytes, but not in skeletal muscle cells in vitro, whereas another PPARg ligand, darglitazone, stimulated LXRa expression in rat epidydimal adipose tissue in vivo [74]. Two PPARg agonists, troglitazone and rosiglitazone, administered orally, increased LXRa expression in rabbit renal glomeruli [172]. Pioglitazone administered for three weeks at a dose of 30 mg/day increased LXRa expression in subcutaneous adipose tissue in non-diabetic insulin-resistant non-obese subjects [59].
Insulin increases LXRa expression in the liver both in vitro and in vivo and it is suggested that the stimulatory effect of insulin on hepatic lipogenesis may be partially mediated via LXRs [160]. 17b-estradiol reduces LXRa expression in cultured human THP-1 macrophages in vitro [84]. In addition, a single dose of estradiol decreased LXRa (but not LXRb) mRNA level in mice liver and white adipose tissue [100].
Several studies have demonstrated that the inflammatory reaction induced by bacterial lipopolysaccharide (LPS) reduces the expression of LXRa and its heterodimeric partner, RXRa, in the liver, kidney, and adipose tissue both in vitro and in vivo [11,47,79,80,97,169]. This effect is reproduced by proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b). In contrast, interleukin-10, an anti-inflammatory and atheroprotective cytokine, stimulates LXRa in cultured THP-1 macrophages [107].
In addition, LXRa expression is controlled by an auto-regulatory mechanism. The human LXRa gene promoter contains three functional LXREs, one of which is strongly activated by both LXRa and LXRb [93]. Both natural and synthetic LXR agonists increase LXRa, but not LXRb, gene expression in human macrophages, adipocytes, and hepatocytes [170]. This autoregulatory mechanism may be responsible for the strong up-regulation of LXRa induced by lipid loading of macrophages. Resting macrophages contain mainly LXRb, whereas in lipid-loaded cells the expression of LXRa markedly increases while the level of LXRb remains stable, presumably due to the upregulation of LXRa gene expression by cholesterol-derived LXR agonists [88]. Initially it was suggested that the autoregulation of LXRa is specific to humans. However, Ulven et al. [161] observed that T0901317 increased the amount of LXRa mRNA in mouse white adipose tissue. Nevertheless, murine LXRa is not autoregulated in other cell types, such as macrophages and hepatocytes.
5.2. Posttranslational regulation of LXR activity
Chen et al. [37] recently demonstrated that LXRa is phosphorylated at Ser198 by mitogen-activated protein kinases (MAPK). The functional significance of this phosphorylation is unclear since the phopshorylated and non-phosphorylated receptors have identical transcriptional activities. However, it should be mentioned that the MAPK consensus phosphorylation site within the LXRa molecule is conserved among species and is also contained in the LXRb, which suggests that phosphorylation may have some functional implications.
Cyclic AMP stimulates the binding of LXRa to CNRE (see above); however, the mechanism of this effect is unclear. In particular, it is unknown if cAMP affects the conformation of LXRa (directly or by stimulating its phosphorylation by protein kinase A) or acts on CNRE, increasing its affinity for LXRa. On the other hand, some data suggest that cAMP synthesized in response to dopamine D1-like receptor stimulation inhibits classical LXR/RXR-LXRE-mediated signaling in neurons [141]. Recently it was demonstrated that protein kinase A phosphorylates LXRa at two sites, Ser195– Ser196 and Thr200–Ser201, which impairs its dimerization with RXR, DNA-binding, and transcriptional activity [175].
Other nuclear receptors which form heterodimers with RXR can inhibit LXR signaling by competing with LXRs for the limited pool of their common dimeric partner. For example, vitamin D receptor (VDR) antagonizes the transcriptional activity of LXRa when stimulated with its ligand, 1,25-dihydroxycholecalciferol [71]. Recent studies indicate that apart from 1,25-dihydroxycholecalciferol, vitamin D receptor may be activated by litocholic acid [105]. Since LXR stimulates the formation of bile acids, inhibiting its activity through the litocholic acid-VDR pathway may be a negative feedback mechanism which prevents the overproduction of potentially toxic bile acids. Triiodothyronine receptor, TRb, and farnesoid X receptor (FXR) also suppress LXR-mediated signaling by quenching RXR [178].
Activin receptor-like kinase (ALK-1) is a plasma membranebound serine/threonine protein kinase belonging to a transforming growth factor-b (TGF-b) receptor family, which is specifically expressed in endothelial cells. Activated ALK-1 phosphorylates LXRb, but not LXRa, and induces its translocation from the nucleus to the cytosol. In addition, LXRb inhibits ALK-1-dependent signaling. These data suggest that significant cross-talk between LXRb and the TGF-b receptor superfamily exists in vascular tissue [114].
The major thyroid hormone receptor expressed in the liver, TRb1, may bind not only to its cognate sequence, thyroid hormone response element (TRE), but also to LXRE within the promoter region of at least two LXR target genes, sterol regulatory element binding protein-1c (SREBP-1c) [76] and cholesterol 7a-hydroxylase (CYP7A1) [60]. In the absence of triiodothyronine (T3), TRb1/RXR heterodimer binds to LXRE and preferentially associates with co-repressors, thus suppressing LXR-stimulated transcription. In the presence of T3, TRb1 stimulates the transcription of CYP7A1 gene. However, the concentration of T3 required to stimulate the LXR target gene by TRb1 is higher than that required to stimulate transcription through the TRb1-TRE-dependent mechanism [60,76]. Neither unliganded nor oxysterol-bound LXRa has any effect on T3-induced gene expression. Moreover, LXR is unable to cross-bind with the TRE [76].
5.3. LXR and PPAR
The interaction between LXR and PPAR is probably cell specific and, in general, very complex. First, as mentioned above, stimulation of PPARa and PPARg may increase LXR gene expression in certain cell types. On the other hand, expression of PPAR may be induced by LXR through the LXRE contained in its promoter region. For example, Seo et al. [143] demonstrated that T0901317 increased PPARg expression in cultured 3T3-L1 adipocytes in vitro as well as in adipose tissue and liver of T0901317-treated mice.
At the posttranslational level, PPAR may inhibit the LXR signaling and vice versa by competing for the limited pool of their common heterodimeric partner, RXR [110]. Transfection of human hepatoma HepG2 cells or human embryonic kidney HEK293 cells with PPARa or PPARg inhibits LXR-mediated signaling even in the absence of PPAR ligands [178]. Stimulation of PPARa or PPARg with Wy14643 or pioglitazone, respectively, enhanced this inhibitory effect, whereas overexpression of RXR abolished this inhibition. On the other hand, stimulation of LXR by T0901317 or 22(R)-HC inhibits PPARa-induced fatty acid oxidation through a similar mechanism [66]. In addition to competing with PPARa for a common pool of RXR, LXRa may inhibit PPARa signaling by forming a nonfunctional LXRa/PPARa heterodimer which is unable to bind to either LXRE or PPRE [113]. A unique mechanism of PPARa-LXRa interaction was described in the regulation of the murine cholesterol 7a-hydroxylase gene (CYP7A1). The CYP7A1 promoter contains overlapping PPRE and LXRE sequences. Therefore, whereas stimulation of either of these receptors alone enhances gene expression, PPARa agonists inhibit LXR-induced transcription and vice versa by forming the LXRa-PPARa heterodimer which binds to this overlapping sequence and blocks the binding of either LXRa/RXR or PPARa/RXR heterodimer [54].
Despite these in vitro studies, the antagonism between PPAR and LXR in vivo remains elusive. Anderson et al. [5] demonstrated that treatment of mice with Wy14643 or T0901317 changed the expressions of 49 genes in the liver, but 48 of them were regulated in the same direction. In addition, of 64 genes downregulated in PPARa-null mice (i.e. constitutively stimulated by PPARa in wild-type animals), only one was downregulated by T0901317. These data question the functional antagonism between these receptors, at least in the liver, and suggest that PPARa and LXR may in fact have many overlapping activities.
5.4. Effect of oxidative stress on LXR signaling
Oxidatively modified plasma low-density lipoproteins (oxLDL) have a complex cell-specific effect on LXR signaling. For example, loading cultured macrophages with oxLDL stimulates LXR signaling because oxidized fatty acids activate PPARg and increase LXRa expression [146]. However, in cultured human umbilical vein endothelial cells, oxLDL diminishes 27-HC production by reducing CYP27 activity and thus inhibits LXR signaling. In contrast, loading endothelial cells with native (non-oxidatively modified) LDL stimulates 27-HC formation and LXR signaling by providing more cholesterol substrate [186]. In addition, enhanced lipid peroxidation induced by iron and ascorbate reduced LXRa and LXRb gene expression in cultured human THP-1 macrophages [107]. The main mechanisms regulating LXR expression and activity are summarized in Table 1.
6. ROLE OF LXRS IN CHOLESTEROL METABOLISM
LXRs sense excess cholesterol and trigger various adaptive mechanisms protecting the cells from cholesterol overload. Activation of LXRs results in: (1) stimulation of cholesterol removal from the cell, transport to the liver, and biliary excretion, processes referred to together as reverse cholesterol transport (RCT), (2) inhibition of intestinal cholesterol absorption, and (3) inhibition of cholesterol synthesis and uptake by the cells. The effects of LXRs on reverse cholesterol transport and excretion as well as on intestinal cholesterol absorption are presumably the major mechanisms, whereas those on cholesterol uptake and synthesis are weak and play only a minor role.
6.1. Reverse cholesterol transport
Reverse cholesterol transport (RCT) is cholesterol trafficking from peripheral tissues to the liver, where it is excreted in the bile as unchanged cholesterol or after conversion to bile acids. RCT is initiated by cholesterol removal from the cell to high-density lipoproteins (HDLs) or to lipid- free apolipoproteins such as apoA-I or apoE. Within HDLs, most of the free cholesterol is esterified by lecithin: cholesterol acyltransferase (LCAT), and cholesterol esters are then transported to the liver either in HDLs or in apoB-containing lipoproteins (VLDLs and LDLs), to which they are first transferred by cholesterol ester transporting protein (CETP).
Recently, Naik et al. [117] demonstrated that if mice are injected with macrophages previously loaded with titrated cholesterol and then are treated with GW3965 for 10 days, fecal excretion of cholesterol tracer is markedly higher and excretion of titrated bile acids tends to be higher than in vehicle- treated animals. These data clearly indicate that this LXR agonist stimulates cholesterol transport to the liver for subsequent excretion and/or metabolism in vivo.
Most, if not all, steps of RCT are stimulated by LXRs. First, LXRs up-regulate the expression of transporters involved in cholesterol removal from plasma membrane to extracellular acceptors, the ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). ABCA1 and ABCG1 are abundant in macrophages where they prevent foam cell formation by removing excess cholesterol, but they are also expressed in most other cell types, including hepatocytes, enterocytes, adipocytes, and skeletal muscle cells. ABCA1 is a full transporter, i.e. it operates as a single molecule and transfers both cholesterol and phospholipids from plasma membranes to small discoid-shape pre-HDL or to lipidfree apoA-I. Thus, apart from RCT, ABCA1 is also involved in the formation of nascent HDL particles in the liver and small intestine. Deficiency of ABCA1 is responsible for Tangier disease, a rare inherited disorder associated with a very low level of HDLs, overaccumulation of cholesterol in peripheral tissues, and premature atherosclerosis. In contrast, ABCG1 is a half-transporter, i.e. it operates as a homodimer and transfers cholesterol to HDLs but not to lipid-free apoA-I [29,86].
Multiple studies have demonstrated that LXR agonists increase the expression of ABCA1 and ABCG1 by binding to the LXREs within their genes, which is accompanied by enhanced cholesterol efflux from various cell types both in vitro and in vivo [42,78,153,162]. In particular, the expression of ABCG1 may be increased up to 1000-fold by natural and synthetic LXR agonists [139,162]. LXR agonists not only stimulate the expression of ABCG1, but also induce its redistribution from intracellular stores to the plasma membrane, further facilitating cholesterol efflux [167]. In peritoneal macrophages obtained from ABCG1- null mice, T0901317 normally stimulates cholesterol efflux to apoA-I, but fails to stimulate cholesterol efflux to HDLs [77]. In addition, ABCG1-specific small interfering RNA (siRNA) blocked HDL-mediated cholesterol efflux [167]. These data suggest that ABCG1 has a critical role in cholesterol efflux to HDLs, but not in the formation of these lipoproteins. Indeed, the plasma lipid profile is normal in ABCG1-null mice, but large amounts of cholesterol accumulate in macrophages/foam cells in various tissues of these animals [77]. In contrast, in ABCA1-null macrophages, T0901317 failed to stimulate cholesterol transport to apoA- 1, but normally stimulated its efflux to HDLs.
Cholesterol loading of the cell results in the increased formation of oxysterols, which stimulate LXRs and enhance cholesterol efflux through these transporters, thus providing the regulatory feedback mechanism maintaining a constant cholesterol content [94]. Engel et al. [46] demonstrated that 22(R)-HC and 9cRA increase the expression of ABCG4, a half-transporter homologous to ABCG1, in human monocyte-derived macrophages. The precise role of ABCG4 is not clear, but it is suggested that it forms a heterodimer with ABCG1. However, ABCG4 is not essential for LXR-stimulated cholesterol efflux since cholesterol export from ABCG4–/– macrophages is normal [167]. Recently, Wang et al. [166] reported that various ABC transporters may be involved in the efflux of cholesterol from different intracellular pools. In particular, cholesterol delivered by intact LDL through the LDL receptor-dependent pathway is subsequently removed by the ABCG1/ ABCG4 heterodimer, whereas cholesterol derived from modified LDL, which entered the cell through the scavenger receptor, is exported by ABCA1. In contrast to ABCA1, ABCG1, and ABCG4, the expression of ABCG2 is not regulated by LXRs. Thus, ABCG2 seems to be a constitutive cholesterol exporter [46].
LXRs are also involved in the regulation of intracellular cholesterol traffic. Before efflux, cholesterol has to be transported from the endosomal compartment to the plasma membrane. This process is mediated by two carriers, Niemann-Pick C1 (NPC1) and C2 (NPC2) proteins. LXR agonists increase the expression of NPC1 and NPC2 and thus stimulate the redistribution of cholesterol from the endosomal compartment to the plasma membrane, where it becomes available for efflux to extracellular acceptors. Indeed, the stimulation of cholesterol efflux by T0901317 or GW3965 was markedly suppressed by siRNA specific to either NPC1 or NPC2 [138]. Although LXR agonists have no effect on the expression of acyl-CoA: cholesterol acyltransferase- 1 (ACAT-1), a major intracellular cholesterolesterifying enzyme, they reduce the rate of cholesterol esterification by removing cholesterol from the intracellular pool available for ACAT-1 to the plasma membrane.
Scavenger receptor type B1 (SR-B1) is a specific HDL receptor expressed in the liver and, to a lesser extent, in other tissues. Hepatic SR-B1 is essential for the delivery of cholesterol esters from HDLs to hepatocytes. In human hepatoma HepG2 cells, 22(R)-HC increased SR-B1 mRNA and protein levels [106]. This effect resulted from the binding of the LXR/RXR dimer to the LXRE within the promoter region of SR-B1 gene. Until now, no study has addressed the regulation of hepatic SR-B1 by LXR in vivo. Yu et al. [181] demonstrated that 25-HC reduces SR-B1 expression in human and murine macrophages and in human umbilical vein endothelial cells. Although this effect may be beneficial by decreasing the uptake of oxidized LDLs, it is preserved in cells lacking both LXR isoforms and thus is clearly LXR-independent. In contrast, neither T0901317 nor 24(S)-HC had any effect on SR-B1 expression in porcine brain capillary endothelial cells [123].
24(S)-hydroxycholesterol, an endogenous LXR agonist synthesized in the brain, stimulates cholesterol efflux from choroid plexus epithelial cells to extracellular apoE by increasing the expression of ABCA1, ABCG1, ABCG4, and ABCG5 [52]. Since this effect was observed only in the apical membrane directed toward the cerebrospinal fluid, which lacks HDLs, it may represent a unique HDL- and apoA-I-independent mechanism of cholesterol removal. In addition, 24(S)-HC and GW3965 increase the expression of ABCA1, ABCG1, and apoE in astrocytes, but not in neurons. These data suggest that 24(S)-HC of neuronal origin may stimulate apoE-mediated cholesterol efflux from the neighboring glial cells [1]. Although apoE-mediated cholesterol efflux is not involved in the net export of cholesterol from the brain, it may be important for the redistribution of cholesterol between various brain regions. This process is essential during development and neuronal injury, because cholesterol is required for neurite outgrowth and synaptogenesis.
6.2. Cholesterol metabolism to bile acids
The first and rate-limiting enzyme of hepatic bile acid synthesis is cholesterol 7a-hydroxylase (CYP7A1). Promoter regions of mouse and rat CYP7A1 genes contain LXRE, and their transcription is potently up-regulated by natural and synthetic LXR agonists [92,111]. LXRE of CYP7A1 gene binds LXRa more potently than LXRb, and therefore LXRa–/– mice, but not LXRb–/– animals, accumulate large amounts of cholesterol in the liver in response to a high-cholesterol diet. This is accompanied by hepatomegaly and severe liver damage. LXRa–/– mice do not exhibit any increase in CYP7A1 expression when switched to a cholesterol-rich diet nor are they able to increase bile acid synthesis and fecal excretion [126].
In contrast to rat and mice, human CYP7A1 gene does not contain the LXRE and its transcription is not up-regulated by LXR agonists [39,55]. This species difference is responsible, at least in part, for much greater susceptibility of humans to dietary-induced hypercholesterolemia [111]. Indeed, cholesterol 7a-hydroxylase is not up-regulated in response to cholesterol feeding in mice expressing human CYP7A1, and these animals easily develop hypercholesterolemia when challenged with a high-cholesterol diet [35].
CYP7A1 is also a target for FXR, which inhibits its expression by stimulating the synthesis of a small heterodimeric partner (SHP) protein. FXR is a specific receptor for bile acids and regulates their formation in a negative feedback manner. FXR inhibits CYP7A1 expression in all known mammalian species. Goodwin et al. [55] demonstrated that the LXR/RXR heterodimer directly activates SHP expression in human hepatocytes, leading to the suppression of CYP7A1 synthesis in response to cholesterol loading. It is suggested that this mechanism evolved in humans to suppress cholesterol absorption from the intestine (by limiting the formation of bile acids and the emulsification of alimentary lipids). However, this mechanism becomes inefficient when humans are exposed to a high-cholesterol diet, which ultimately results in cholesterol overabsorption despite the down-regulation of the intestinal bile acid pool.
Although in vitro FXR agonists stimulate SHP and inhibit the transcription of CYP7A1 gene in rat hepatocytes, feeding these animals a high-cholesterol diet results in the up-regulation of this enzyme, while hepatic expression of SHP does not change [55]. It has been shown that FXR is not activated by a high-cholesterol diet in the rat because the hepatic bile acid pool does not increase; although their synthesis is stimulated, this is balanced by increased excretion [174]. Therefore, although at the molecular level rat CYP7A1 is up-regulated by LXR and down-regulated by FXR, the former mechanism predominates in vivo when animals are exposed to a high-cholesterol diet. However, if the high-cholesterol diet is supplemented by exogenous cholic acid, FXR is activated, SHP expression is increased, and CYP7A1 expression is reduced, resulting in impaired cholesterol metabolism and hypercholesterolemia [174].
Although rabbit CYP7A1 gene contains LXRE and its expression is stimulated by T0901317 and 22(R)-HC in vitro [144], high-cholesterol diet fails to induce CYP7A1 in the rabbit in vivo. Xu et al. [173] demonstrated that if rabbits are exposed to a high-cholesterol diet for only one day, hepatic CYP7A1 is up-regulated, presumably through the LXR-dependent mechanism, whereas the expression of the FXR target SHP does not change. However, if the high-cholesterol diet is applied for 10 days, SHP is up-regulated and the expression of CYP7A1 is reduced, which indicates that the positive LXR-mediated regulation is overridden by the inhibitory effect of FXR [144,173]. Therefore, hypercholesterolemia easily develops if rabbits are fed a high-cholesterol diet. The regulation of CYP7A1 by LXR and FXR in various mammalian species is summarized in Table 2.
Table 2. Regulation of hepatic CYP7A1 gene expression in various mammalian species

6.3. Bile acid transport and metabolism
22(R)-HC stimulates the expression of the bile salt export pump (BSEP), which drives bile acid transport from hepatocytes to bile canaliculi in primary human hepatocytes and in Huh7 hepatoma cells. However, this effect is mediated by FXR rather than LXR. 22(R)-HC binds to a part of the FXR ligand-binding domain at a place distinct from its cognate ligands, bile acids. LXR agonists stimulate the expression of intestinal bile acid-binding protein (I-BABP), which is involved in the absorption of bile acids from intestinal lumen to the portal blood [90]. Interestingly, this effect is mediated by LXR binding to the FXRE in the promoter region of the I-BABP gene.
In human hepatocytes, T0901317 up-regulates UDP-glucuronyltransferase 1A3 (UGT1A3), which glucuronidates chemodeoxycholic and litocholic acids (CDCA and LCA) at the C-24 position, thus increasing their water solubility and allowing urinary excretion [163]. A similar effect is observed in transgenic mice expressing human UGT1A3. Apart from glucuronidation, CDCA and LCA may be hydroxylated at the 6a position to generate hyocholic acid (HCA) and hyodeoxycholic acid (HDCA), respectively. This reaction is inhibited by LXR agonists. Both HCA and HDCA are specific LXRa agonists and thus inhibit their own formation through a negative feedback mechanism. In summary, stimulation of LXR shifts CDCA and LCA metabolism toward 24-glucuronides by UGT1A3 at the expense of 6a-hydroxylation. In contrast, FXR stimulates CYP3A4 and UGT2B4, leading to predominant formation of 6a-glucuronides of HCA and HDCA.
6.4. Intestinal cholesterol absorption
Alimentary cholesterol is absorbed in the small intestine. An important role in this process is played by the Niemann- Pick C1-like 1 protein (NPC1L1) contained in the apical membranes of enterocytes. Next the majority of cholesterol is esterified inside the enterocyte by ACAT-2 and is incorporated into chylomicrons. Some cholesterol is exported through the ABCA1 contained in the basolateral membrane to apoA-I; the process is essential for intestinal HDL formation (Figure 9). In addition, a substantial part of the intracellular cholesterol is back-extruded from the enterocyte to the intestinal lumen through the ABCG5/ABCG8 heterodimer contained in the apical membrane [165].
Figure 9. Intestinal cholesterol absorption (red arrows), intestinal phytosterol handling (green arrows), and the role of enterocytes in fecal excretion of cholesterol delivered from peripheral tissues by HDLs (i.e. alternative reverse cholesterol transport, blue arrows). Cholesterol is absorbed from bile micelles through the apical membrane NPC1L1 protein. Most of it is subsequently esterified by ACAT-2, and cholesteryl esters are incorporated into chylomicrons (CHM), which are exocytozed and enter the lymphatic capillaries. Some cholesterol is extruded to the intestinal lumen through the apical ABCG5/ABCG8 heterodimer and the minority of cholesterol is extruded through the basolateral ABCA1 to enter the HDL fraction, in part formed locally in the intestine from locally generated apoAI. Alimentary phytosterols are absorbed by NPC1L1, but are not esterified; most of them are rapidly extruded to the gut lumen through the ABCG5/ABCG8 complex and some phytosterols are transferred to HDLs by basolateral ABCA1. In addition, the intestine may drive the removal of peripheral tissue-derived cholesterol from HDLs to the feces through the concerted action of basolateral ABCA1 and apical ABCG5/ABCG8. LXR agonists inhibit NPC1L1 and increase ABCA1, ABCG5, and ABCG8

In 2000, Repa et al. [137] first demonstrated that T0901317 reduced intestinal absorption of dietary cholesterol. Because this effect was accompanied by the increased expression of ABCA1 in the small intestine, it was initially suggested that this transporter drives cholesterol removal from the enterocytes to the intestinal lumen and thus reduces the net cholesterol absorption [137]. However, this possibility is unlikely since ABCA1 is contained mainly in the basolateral membrane of intestinal cells and the effect of LXR agonists on fecal cholesterol excretion is preserved in ABCA1 knockout mice [130]. Indeed, LXR agonists stimulate cholesterol recycling from the enterocyte to the intestinal lumen by up-regulating ABCG5 and ABCG8 [134]. Fecal cholesterol content is increased, whereas net intestinal cholesterol absorption is reduced in mice overexpressing ABCG5 and ABCG8, whereas the opposite is observed in ABCG5/ABCG8 double-knockout animals [182].
Apart from the intestine, ABCG5 and ABCG8 are abundantly expressed in the canalicular membrane of hepatocytes, where they drive cholesterol transport to the bile. Hepatic ABCG5 and ABCG8 are also stimulated by LXR agonists, and this results in enhanced biliary cholesterol excretion [182]. In contrast to wild-type animals, T0901317 does not stimulate biliary cholesterol excretion and fails to reduce fractional cholesterol absorption in ABCG5/ABCG8 double-knockout mice [182].
However, the increase in fecal cholesterol by LXR agonists is not solely dependent on biliary cholesterol excretion. Indeed, GW3965 does not stimulate biliary cholesterol content, but increases fecal cholesterol loss in mice lacking the multidrug resistance protein-2 (Mdr-2, ABCB4) involved in the export of phospholipids from hepatocytes to bile canaliculi [85]. Interestingly, GW3965 also effectively increases the excretion of radiolabeled cholesterol from plasma to the feces in these animals. It is suggested that apart from the liver, the intestine is an alternative organ involved in reverse cholesterol transport and excretion. According to this hypothesis, HDLs may deliver cholesterol from peripheral tissues directly to the intestine, where it is removed to the gut lumen through the concerted action of basolateral ABCA1 and apical ABCG5/ABCG8 heterodimer (Figure 9) [85].
Recently, Duval et al. [44] demonstrated that T0901317 and GW3965 decrease the expression of NPC1L1 protein in mouse intestine in vivo and in human enterocyte cell culture in vitro, thus completing a complex mechanism through which LXRs reduce cholesterol absorption (Figure 9).
6.5. Effect of LXRs on intestinal HDL formation
Apart from the liver, the small intestine is a major HDLgenerating organ in the body. Although LXR agonists inhibit cholesterol absorption in an ABCA1-independent manner, they do stimulate this transporter in enterocytes and enhance intestinal HDL formation. Indeed, LXR agonists stimulate apoA-I-mediated cholesterol efflux from the basolateral, but not from the apical membrane of enterocytes, and have no effect on the formation of chylomicrons [116,121]. Intestine-specific deletion of ABCA1 results in an about 30% reduction of plasma HDL [23]. Tissue-specific stimulation of intestinal ABCA1 by LXR agonists raises the plasma HDL level. Indeed, GW3965 increases plasma HDL in wild-type mice as well as in animals lacking hepatic ABCA1, but fails to do so in mice lacking ABCA1 selectively in the small intestine [24].
6.6. Effect of LXRs on plant sterol absorption
Although plant sterols are almost as abundant as cholesterol in food, only a small fraction of them is absorbed in the intestine for two reasons. First, plant sterols are much more effectively exported by the ABCG5/ABCG8 heterodimer. In addition, plant sterols are very poor substrates for esterification by intestinal ACAT-2. Thus, most of plant sterols reaching the enterocyte are rapidly removed to the intestinal lumen (Figure 9). Any absorbed plant sterols are also rapidly excreted to the bile by hepatic ABCG5/ABCG8 complex. Therefore, the plasma concentration of plant sterols is normally very low [62]. Mutation of either the ABCG5 or ABCG8 gene results in sitosterolemia (phytosterolemia), a rare inherited recessive disease characterized by a very high level of plant sterols in plasma and tissues, moderate hypercholesterolemia, and accelerated atherosclerosis, presumably related to deposition of plant sterols in the arterial wall.
Under normal conditions, LXR agonists limit intestinal absorption of plant sterols and increase their biliary excretion by stimulating ABCG5 and ABCG8. However, in ABCG5 knockout mice [129] and in ABCG5/ABCG8 double-knockout mice [182], LXR agonists paradoxically increase the plasma concentration of phytosterols. This is most likely associated with the unopposed stimulation of ABCA1-driven basolateral phytosterol efflux from the enterocyte to HDLs (Figure 9). Indeed, the plasma level of plant sterols is lower in ABCA1-deficient mice, and it was demonstrated that T0901317, 22(R)-HC, and 9cRA stimulate basolateral apoA-I-mediated efflux of b-sitosterol from cultured intestinal epithelial cells [48]. ABCA1 does not discriminate between cholesterol and plant sterols. Because plant sterols are not esterified by ACAT-2 and are not incorporated into chylomicrons, they are absorbed exclusively via a ABCA1-dependent route. These data suggest that LXR agonists could have a paradoxical, undesirable effect on plasma plant sterols in patients with sitosterolemia, and possibly also in the much more frequent asymptomatic ABCG5 or ABCG8 mutant heterozygotes.
6.7. Cholesterol synthesis and uptake
Cellular cholesterol content depends on the balance of three processes: 1) intracellular synthesis, 2) uptake from plasma lipoproteins, mainly LDLs, and 3) removal from the cell to plasma lipoproteins, mainly HDLs. Cholesterol synthesis is precisely regulated to maintain a constant cholesterol content and is thus adjusted to the remaining two processes. Due to the potent effect of LXR agonists on cholesterol removal from the cell, it is difficult to separate any direct effect of these receptors on cholesterol synthesis from adaptor changes induced by altered uptake and/or removal.
Several key enzymes in the cholesterol biosynthesis pathway, including 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, are stimulated by the sterol regulatory element binding protein-2 (SREBP-2). SREBPs are transcription factors synthesized as the inactive precursors which reside in the endoplasmic reticulum and are subsequently activated by proteolysis, move to the nucleus, and stimulate the expression of target genes. Three isoforms of SREBPs were identified; two of them (SREBP-1a and SREBP-1c) are encoded by a single gene, whereas the third, SREBP-2, is encoded by a separate gene. SREBP-1a stimulates the expression of genes involved in both cholesterol and fatty acid synthesis, SREBP-1c stimulates lipogenesis, and SREBP-2 stimulates cholesterol-synthesizing enzymes and LDL receptor. SREBP-2 is activated in response to cholesterol depletion and stimulates compensatory upregulation of cholesterol uptake and synthesis [31].
LXRa-null mice are characterized by a higher expression of SREBP-2 as well as of several of its target genes, including HMG-CoA synthase and reductase, farnesylpyrophosphate synthase, and squalene synthase in the liver [126]. The similar, although much smaller, up-regulation of cholesterol- synthesizing enzymes is observed in LXRb-null mice [3]. In addition, administration of T0901317 reduces the hepatic expression of HMG-CoA synthase and squalene synthase in wild-type mice [142]. These data suggest that LXRs inhibit cholesterol synthesis. However, it should be kept in mind that natural LXR agonists, oxysterols, may affect cholesterol synthesis in an LXR-independent manner, e.g. by inhibiting the cleavage of SREBP-2. In addition, stimulation of cholesterol efflux by the LXR agonists may cause a compensatory up-regulation of cholesterol synthesis in certain cell types, such as macrophages. For example, T0901317 and GW3965 enhance cholesterol synthesis as well as increase LDL-receptor expression in human hepatoma HepG2 cells, probably by stimulating cholesterol efflux and activating the SREBP-2-dependent pathway. In contrast, natural agonists have no (22(R)-HC) or slight inhibitory (24(S),25-EC) effect on cholesterol production, most likely by directly suppressing SREBP-2 processing [6]. Therefore, the interpretation of data about the role of LXRs in the regulation of cholesterol synthesis is difficult. In general, it is assumed that the effect on cholesterol synthesis plays only a minor role in the regulation of cellular sterol homeostasis by LXR ligands. Recently, Ishimoto et al. [67] demonstrated that T0901317 increases the expression of LDL-receptor in the human hepatoblastoma Huh- 7 cell line through the LXRE contained in the promoter of its gene. However, it is unclear if this effect also occurs in the intact liver or in extrahepatic tissues.
7. OTHER EFFECTS ON LIPID METABOLISM
7.1. Lipogenesis
In 2000, Schultz et al. [142] first demonstrated that treatment with T0901317 markedly increased hepatic triglyceride content and plasma triglyceride concentration in mice and hamsters. Although the effect on plasma triglycerides was transient, that on hepatic triglycerides was persistent and lead to severe liver steatosis and dysfunction. In addition, plasma triglycerides are about fourfold lower in LXRa/LXRb double-knockout mice than in wild-type animals.
LXR agonists markedly stimulate fatty acid synthesis (lipogenesis) in hepatocytes. This effect is partially mediated by increased expression of SREBP-1c, which subsequently binds to the sterol response element (SRE) within the promoter region of genes encoding various lipogenic enzymes [135]. In rat hepatoma cells, baseline expression of SREBP-1c is maintained by the endogenous oxysterol- LXR pathway since inhibition of oxysterol formation reduces SREBP-1c synthesis [43]. Yoshikawa et al. [179] identified two LXREs within the SREBP-1c gene promoter and demonstrated that LXR as well as RXR agonists increase its transcriptional activity. In addition, LXR directly (in a SREBP-1c independent manner) regulates the expression of several lipogenic enzymes, including acetyl-CoA carboxylase (ACC) [155], fatty acid synthase (FAS) [73], and stearoyl-CoA desaturase-1 (SCD-1) [168], by binding to the LXREs in the regulatory regions of ACC, FAS, and SCD-1 genes, respectively. SCD-1 forms the double bond at the n- 9 position of saturated fatty acids, thus converting saturated stearoyl-CoA and palmitoyl-CoA to monounsaturated oleoyl- CoA and palmitoleoyl-CoA, respectively. Indeed, LXR agonists increase the ratio of monounsaturated to saturated fatty acids (“desaturation index”) in cellular lipids and plasma lipoproteins [185]. Chu et al. [41] demonstrated that SCD-1 deficiency protects against LXR-induced increase in plasma triglyceride and HDL-cholesterol levels. Thus, SCD-1 is crucial for the lipogenic effect of LXRs.
Treating wild-type mice with T0901317 increases SREBP- 1c, ACC, FAS, and SCD-1 gene expression in the liver [142]. This effect is preserved in LXRb–/–, but not in LXRa–/– mice. In addition, basal levels of SREBP-1c, ACC, FAS, and SCD-1 are reduced in LXRa–/– mice. These data suggest that LXRa is a major isoform responsible for hepatic lipogenesis.
Grefhorst et al. [56] demonstrated that LXR agonists stimulate the production of triglyceride-rich, large VLDL particles in the liver. Although the number of VLDL particles formed does not change, their diameter increases due to the higher amount of triglycerides per particle. In animals treated with LXR agonists, the plasma triglyceride concentration increases only transiently because VLDL metabolism is simultaneously stimulated, presumably due to the increase in lipoprotein lipase (see below). In addition, T0901317 stimulates peroxisomal b-oxidation of very-longchain fatty acids in the liver [64].
Although enhanced lipogenesis is clearly undesirable if one considers the potential therapeutic application of LXR agonists, it is a logical component of a complex response to cholesterol excess because it enables the conversion of more toxic free cholesterol to less toxic cholesterol esters. Indeed, monounsaturated fatty acids generated by SCD-1 are preferable substrates for ACAT. In addition, lipogenesis may provide components essential for cholesterol removal from the cell, such as triglycerides required for VLDL assembly in the liver or phospholipids required for HDL formation.
It should be emphasized that synthetic LXR agonists induce lipogenesis much more potently than cholesterol excess. Although cholesterol excess, ultimately resulting in increased oxysterols, stimulates SREBP-1c synthesis through the LXR-dependent mechanism, cholesterol itself as well as certain oxysterols inhibit proteolytic processing of the inactive SREBP-1c precursor to its mature active form. Due to these two opposing effects, cholesterol does not stimulate lipogenesis dramatically. In contrast, synthetic nonsteroid LXR agonists increase SREBP-1c synthesis while having no inhibitory effect on its processing, which results in supraphysiological stimulation of fatty acid synthesis.
Carbohydrate response element binding protein (ChREBP) is a glucose-sensitive transcription factor which stimulates the expression of lipogenic enzymes when the glucose concentration is high and thus promotes the conversion of excess glucose to lipids. Recently it was demonstrated that LXR agonists stimulate the expression of ChREBP in the liver both in vitro and in vivo [30]. This effect results from the binding of LXR/RXR to the two LXREs in the promoter region of the ChREBP gene. It was demonstrated that the stimulatory effects of T0901317 on FAS, ACC, and SCD-1 were attenuated in ChREBP-knockout mice. In addition to inducing ChREBP expression, T0901317 stimulates its binding to the cognate DNA sequence, carbohydrate response element (CRE). ChREBP-CRE binding is inhibited by the active phosphorylated form of AMPstimulated protein kinase (AMPK), and T0901317 reduces the rate of AMPK phosphorylation, thus removing its inhibitory influence on ChREBP activity [30].
Adiponectin is secreted in large amounts by adipocytes and exerts many beneficial metabolic effects, such as increased insulin sensitivity and stimulation of mitochondrial fatty acid oxidation. Adiponectin reduces hepatic lipogenesis and prevents hepatic steatosis by reducing SREBP-1c expression. Interestingly, 25-HC reduces the expression of adiponectin receptor, AdipoR1, in primary hepatocytes and in cultured human HepG2 cell line [118]. It is unclear if this effect is mediated by LXRs and if it also operates in vivo, but if so, downregulation of adiponectin signaling in the liver could contribute to enhanced lipogenesis.
Zhang et al. [184] demonstrated that LXR agonists stimulate the expression of liver-specific uridine phosphorylase, the rate-limiting enzyme in uridine catabolism. A major metabolic product of uridine catabolism in the liver is b-alanine, which serves as a precursor for fatty acid synthesis. Thus, the effect on uridine phosphorylase could be involved in LXR-induced lipogenesis. The currently known mechanisms of the lipogenic effect of LXRs are summarized in Table 3.
Table 3. Mechanisms involved in lipogenic effect of LXR agonists

Because insulin stimulates LXRa expression in the liver, LXRs may be involved in insulin-induced lipogenesis. Indeed, insulin increases the expression of SREPB-1c and its target lipogenic enzymes. Moreover, the induction of SREBP-1c by insulin requires an intact LXRE in the SREBP-1c gene promoter [34] and is largely abrogated in LXRa/LXRb double-knockout mice [160]. Interestingly, whereas LXR agonists increase the expression of the SREPB-1c precursor, insulin additionally stimulates its cleavage to the mature, transcriptionally active form. Thus LXR agonists and insulin may act synergistically to increase fatty acid synthesis [61]. In vivo, T0901317 stimulates SREBP-1c expression and increases the amount of active mature protein because endogenous insulin is present [61]. Because insulin secretion is proportional to glucose concentration, the net lipogenic effect of LXR agonists depends on glucose availability.
7.2. Apolipoproteins
LXR agonists stimulate the synthesis of apolipoprotein-E in macrophages and in adipose tissue both in vitro and in vivo [89]. In contrast, apoE expression in the liver is not regulated by LXRs. In fact, apoE was the first identified LXR-responsive gene which is regulated in a tissue-specific manner. The stimulatory effect on apoE is greater in human than in murine macrophages [88]. In addition to apoAI, apoE is an alternative extracellular cholesterol acceptor and is thus involved in LXR-stimulated cholesterol efflux. Apart from apoE, LXR agonists stimulate the expression of apolipoproteins C-I, C-II, and C-IV, which also operate as cholesterol acceptors [104].
LXR agonists increase the expression of apolipoprotein D in adipocytes [65]. ApoD is a 29-kDa glycoprotein that is primarily associated with plasma HDL. It is synthesized in many tissues, including spleen, testes, and brain. The physiological function of apoD is unclear and it is not known if apoD is also regulated by LXRs outside the adipose tissue.
The next apolipoprotein regulated by LXRs is apoA-IV. ApoA-IV is synthesized in the intestine and, to a lesser extent, in the liver, and is detected mainly in chylomicrons and in lower amounts in HDLs, as well as a free plasma protein. In HDLs, apoA-IV stimulates LCAT, whereas free plasma apoA-IV facilitates cholesterol efflux from the cells and exerts antioxidant activity. Transgenic overexpression of apoA-IV reduces atherosclerosis in the mouse models, and plasma apoA-IV is inversely correlated with atherosclerosis in humans [132,154]. Although the apoA-IV gene contains the LXRE, LXR agonists stimulate its expression only in hepatocytes, but not in the intestine. In vivo, T0901317 increases HDL-associated apoA-IV, which is presumably of hepatic origin, but has no effect on intestinederived chylomicron-associated apoprotein. Interestingly, apoA-IV acts on the hypothalamic appetite center to reduce food intake. Although LXR agonists have no reported effect on food intake in wild-type mice, T0901317 decreases food intake in Zucker diabetic fatty (ZDF) rat [27]. However, an anorectic effect is exerted by apoA-IV synthesized locally in the brain, and it is unclear if LXR agonists regulate central apoA-IV production.
Apolipoprotein A-V is the only known apolipoprotein downregulated by LXR agonists both in vitro and in vivo [68]. ApoA-V is synthesized in the liver and is incorporated into the HDL and VLDL fractions. Overexpression of apoA-V reduces plasma triglycerides in mice, whereas deletion of apoA-V gene induces hypertriglyceridemia [133]. The hypolipidemic effect of apoA-V is most likely mediated by stimulation of lipoprotein lipase. T0901317 reduces apoAV mRNA level in cultured hepatocytes; however, this is an indirect effect mediated by SREBP-1c rather than by direct binding of LXR/RXR to the apoA-V gene [68].
7.3. Plasma lipoprotein-remodeling transporters
LXR agonists stimulate the expression of two plasma lipoprotein- remodeling proteins, CETP and phospholipid transfer protein (PLTP). CETP is synthesized in the liver and circulates in the HDL fraction. CETP transfers cholesterol esters from HDLs to VLDLs and LDLs in the exchange for triglycerides. Thus, CETP may facilitate cholesterol transport to the liver. However, the role of CETP in plasma lipoprotein metabolism and atherogenesis is controversial, because it also contributes to high LDL-cholesterol level in humans and rabbits, whereas species lacking CETP, such as rats and mice, have very low levels of LDLs [82].
LXR agonists increase hepatic CETP synthesis and plasma CETP concentrations [101]. Consistent with the role of CETP outlined above, LXR agonists markedly elevate plasma HDLcholesterol in species lacking CETP, but have only a weak or no effect on HDLs in CETP-positive animals. In addition, in two CETP-positive species, Syrian hamster and cynomolgus monkey, LXR agonists significantly elevate LDL-cholesterol [58]. In addition, transgenic mice expressing human CETP demonstrate elevation of LDLs and no change in HDLs in response to LXR agonists [72,109].
Phospholipid transfer protein (PLTP) mediates the transport of phospholipids from VLDLs and chylomicron remnants to HDLs or to lipid-poor apoA-I. In addition, PLTP mediates phospholipid transfer between different HDL subfractions, thus generating lipid-poor small pre-b HDLs which are better cholesterol acceptors than large HDL particles. T0901317 increases PLTP activity in plasma as well as PLTP mRNA in the liver, adipose tissue, and intestine, which is accompanied by an increase in phospholipid content in the HDL fraction [26,87]. Stimulation of PLTP may contribute to LXR-induced VLDL production because PLTP is involved in the assembly of VLDLs in hepatocytes [56]. Indeed, the hypertriglyceridemic effect of T0901317 is markedly reduced in PLTP-deficient mice [26]. In addition to the liver, natural and synthetic LXR agonists increase PLTP expression in human and murine macrophages [87,103].
7.4. Enzymes involved in plasma lipoprotein metabolism
Triglycerides and/or phospholipids contained in plasma lipoproteins are hydrolyzed by three lipases expressed on the surface of endothelial cells: lipoprotein lipase (LPL), hepatic lipase (HPL), and endothelial lipase (EL). LPL has a high affinity for triglycerides and hydrolyzes triglyceriderich lipoproteins such as VLDLs and chylomicrons. Mice and human LPL genes contain LXRE and are direct targets for LXRa, but not for LXRb [183]. Interestingly, the stimulatory effect of LXR on LPL expression is restricted to the liver and, to a lesser extent, macrophages. In contrast, LXR agonists have no effect on LPL in adipose tissue.
Endothelial lipase (EL) hydrolyzes plasma phospholipids, including those associated with HDLs. Sovic et al. [152] demonstrated that 24(S)-HC reduces EL mRNA and protein levels in brain capillary endothelial cells. This effect may contribute to the LXR-induced increase in HDL fraction. However, Norata et al. [119] observed increased EL expression in human umbilical vein endothelial cells, human fibroblasts, and HepG2 cells treated with T0901317, but not with 22(R)-HC. Thus the effect of LXRs on EL may be cell specific and remains controversial. Until now, the role of LXRs in the regulation of hepatic lipase, the third enzyme involved in intravascular lipolysis, which is active toward both triglycerides and phospholipids, has not been studied.
CONCLUSIONS
Liver X receptors (LXRs) are nuclear receptors which form heterodimers with the retinoid X receptor and regulate gene expression. LXRs are activated by oxysterols, which are enzymatically or nonenzymatically formed cholesterol derivatives, as well as by glucose. T0901317 and GW3965 are two nonsteroid synthetic LXR agonists used in experimental studies that are more potent that endogenous ones. LXR signaling may also be modulated by changes in receptor expression. LXRs protect the cells from cholesterol overload by stimulating reverse cholesterol transport from peripheral tissues to the liver and its excretion in the bile. In addition, LXR agonists activate lipogenesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory elementbinding protein-1c (SREBP-1c), leading to hypertriglyceridemia and liver steatosis. Other effects of LXRs include stimulation of several apolipoproteins (apo-E, apo-D, apo-AIV) as well as of cholesterol ester transporting protein (CETP) and phospholipid transfer protein (PLTP).
REFERENCES
[1] Abildayeva K., Jansen P.J., Hirsch-Reinshagen V., Bloks V.W., Bakker A.H., Ramaekers F.C., de Vente J., Groen A.K., Wellington C.L., Kuipers F., Mulder M.: 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J. Biol. Chem., 2006; 281: 12799-12808
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[2] Albers M., Blume B., Schlueter T., Wright M.B., Kober I., Kremoser C., Deuschle U., Koegl M.: A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors. J. Biol. Chem., 2006; 281: 4920-4930
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[3] Alberti S., Schuster G., Parini P., Feltkamp D., Diczfalusy U., Rudling M., Angelin B., Bjorkhem I., Pettersson S., Gustafsson J.A.: Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRb-deficient mice. J. Clin. Invest., 2001; 107: 565-573
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[4] Anderson L.M., Choe S.E., Yukhananov R.Y., Hopfner R.L., Church G.M., Pratt R.E., Dzau V.J.: Identification of a novel set of genes regulated by a unique liver X receptor-a -mediated transcription mechanism. J. Biol. Chem., 2003; 278: 15252-15260
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[5] Anderson S.P., Dunn C., Laughter A., Yoon L., Swanson C., Stulnig T.M., Steffensen K.R., Chandraratna R.A., Gustafsson J.A., Corton J.C.: Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor a, retinoid X receptor, and liver X receptor in mouse liver. Mol. Pharmacol., 2004; 66: 1440-1452
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[6] Aravindhan K., Webb C.L., Jaye M., Ghosh A., Willette R.N., DiNardo N.J., Jucker B.M.: Assessing the effects of LXR agonists on cellular cholesterol handling: a stable isotope tracer study. J. Lipid Res., 2006; 47: 1250-1260
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[7] Auboeuf D., Rieusset J., Fajas L., Vallier P., Frering V., Riou J.P., Staels B., Auwerx J., Laville M., Vidal H.: Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-a in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes, 1997; 46: 1319-1327
[PubMed]  
[8] Axelson M., Larsson O.: Low density lipoprotein (LDL) cholesterol is converted to 27-hydroxycholesterol in human fibroblasts. Evidence that 27-hydroxycholesterol can be an important intracellular mediator between LDL and the suppression of cholesterol production. J. Biol. Chem., 1995; 270: 15102-15110
[PubMed]  [Full Text PDF]  
[9] Babiker A., Andersson O., Lindblom D., van der Linden J., Wiklund B., Lutjohann D., Diczfalusy U., Bjorkhem I.: Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J. Lipid. Res., 1999; 40: 1417-1425
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[10] Babiker A., Andersson O., Lund E., Xiu R.J., Deeb S., Reshef A., Leitersdorf E., Diczfalusy U., Bjorkhem I.: Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high density lipoprotein-mediated reverse cholesterol transport. J. Biol. Chem., 1997; 272: 26253-26261
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[11] Beigneux A.P., Moser A.H., Shigenaga J.K., Grunfeld C., Feingold K.R.: The acute phase response is associated with retinoid X receptor repression in rodent liver. J. Biol. Chem., 2000; 275: 16390-16399
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[12] Bjorkhem I.: Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J. Intern. Med., 2006; 260: 493-508
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[13] Bjorkhem I.: Do oxysterols control cholesterol homeostasis? J. Clin. Invest., 2002; 110: 725-730
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[14] Bjorkhem I., Andersson O., Diczfalusy U., Sevastik B., Xiu R.J., Duan C., Lund E.: Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc. Natl. Acad. Sci. USA., 1994; 91: 8592-8596
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[15] Bjorkhem I., Diczfalusy U.: 24(S),25-epoxycholesterol-a potential friend. Arterioscler. Thromb. Vasc. Biol., 2004; 24: 2209-2210
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[16] Bjorkhem I., Diczfalusy U.: Oxysterols: friends, foes, or just fellow passengers? Arterioscler. Thromb. Vasc. Biol., 2002; 22: 734-742
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[17] Bjorkhem I., Lutjohann D., Breuer O., Sakinis A., Wennmalm A.: Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro. J. Biol. Chem., 1997; 272: 30178-30184
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[18] Bodin K., Andersson U., Rystedt E., Ellis E., Norlin M., Pikuleva I., Eggertsen G., Bjorkhem I., Diczfalusy U.: Metabolism of 4b-hydroxycholesterol in humans. J. Biol. Chem., 2002; 277: 31534-31540
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[19] Bodin K., Bretillon L., Aden Y., Bertilsson L., Broome U., Einarsson C., Diczfalusy U.: Antiepileptic drugs increase plasma levels of 4b-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4. J. Biol. Chem., 2001; 276: 38685-38689
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[20] Bramlett K.S., Houck K.A., Borchert K.M., Dowless M.S., Kulanthaivel P., Zhang Y., Beyer T.P., Schmidt R., Thomas J.S., Michael L.F., Barr R., Montrose C., Eacho P.I., Cao G., Burris T.P.: A natural product ligand of the oxysterol receptor, liver X receptor. J. Pharmacol. Exp. Ther., 2003; 307: 291-296
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[21] Bretillon L., Lutjohann D., Stahle L., Widhe T., Bindl L., Eggertsen G., Diczfalusy U., Bjorkhem I.: Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface. J. Lipid Res., 2000; 41: 840-845
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[22] Brown A.J., Jessup W.: Oxysterols and atherosclerosis. Atherosclerosis, 1999; 142: 1-28
[PubMed]  
[23] Brunham L.R., Kruit J.K., Iqbal J., Fievet C., Timmins J.M., Pape T.D., Coburn B.A., Bissada N., Staels B., Groen A.K., Hussain M.M., Parks J.S., Kuipers F., Hayden M.R.: Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J. Clin. Invest., 2006; 116: 1052-1062
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[24] Brunham L.R., Kruit J.K., Pape T.D., Parks J.S., Kuipers F., Hayden M.R.: Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ. Res., 2006; 99: 672-674
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[25] Byskov A.G., Andersen C.Y., Nordholm L., Thogersen H., Xia G., Wassmann O., Andersen J.V., Guddal E., Roed T.: Chemical structure of sterols that activate oocyte meiosis. Nature, 1995; 374: 559-562
[PubMed]  
[26] Cao G., Beyer T.P., Yang X.P., Schmidt R.J., Zhang Y., Bensch W.R., Kauffman R.F., Gao H., Ryan T.P., Liang Y., Eacho P.I., Jiang X.C.: Phospholipid transfer protein is regulated by liver X receptors in vivo. J. Biol. Chem., 2002; 277: 39561-39565
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[27] Cao G., Liang Y., Broderick C.L., Oldham B.A., Beyer T.P., Schmidt R.J., Zhang Y., Stayrook K.R., Suen C., Otto K.A., Miller A.R., Dai J., Foxworthy P., Gao H., Ryan T.P., Jiang X.C., Burris T.P., Eacho P.I., Etgen G.J.: Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis. J. Biol. Chem., 2003; 278: 1131-1136
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[28] Carpenter K.L., Taylor S.E., van der Veen C., Williamson B.K., Ballantine J.A., Mitchinson M.J.: Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim. Biophys. Acta, 1995; 1256: 141-150
[PubMed]  
[29] Cavelier C., Lorenzi I., Rohrer L., von Eckardstein A.: Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim. Biophys. Acta, 2006; 1761: 655-666
[PubMed]  
[30] Cha J.Y., Repa J.J.: The liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem., 2007; 282: 743-751
[PubMed]  
[31] Chang T.Y., Chang C.C., Ohgami N., Yamauchi Y.: Cholesterol sensing, trafficking, and esterification. Annu. Rev. Cell. Dev. Biol., 2006; 22: 129-157
[PubMed]  
[32] Chang Y.H., Abdalla D.S., Sevanian A.: Characterization of cholesterol oxidation products formed by oxidative modification of low density lipoprotein. Free Radic. Biol. Med., 1997; 23: 202-214
[PubMed]  
[33] Chawla A., Boisvert W.A., Lee C.H., Laffitte B.A., Barak Y., Joseph S.B., Liao D., Nagy L., Edwards P.A., Curtiss L.K., Evans R.M., Tontonoz P.: A PPARg-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell., 2001; 7: 161-171
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[34] Chen G., Liang G., Ou J., Goldstein J.L., Brown M.S.: Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc. Natl. Acad. Sci. USA, 2004; 101: 11245-11250
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[35] Chen J.Y., Levy-Wilson B., Goodart S., Cooper A.D.: Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. J. Biol. Chem., 2002; 277: 42588-42595
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[36] Chen M., Beaven S., Tontonoz P.: Identification and characterization of two alternatively spliced transcript variants of human liver X receptor a. J. Lipid Res., 2005; 46: 2570-2579
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[37] Chen M., Bradley M.N., Beaven S.W., Tontonoz P.: Phosphorylation of the liver X receptors. FEBS Lett., 2006; 580: 4835-4841
[PubMed]  
[38] Chen W., Chen G., Head D.L., Mangelsdorf D.J., Russell D.W.: Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell. Metab., 2007; 5: 73-79
[PubMed]  
[39] Chiang J.Y., Kimmel R., Stroup D.: Regulation of cholesterol 7a-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRa). Gene, 2001; 262: 257-265
[PubMed]  
[40] Chinetti G., Lestavel S., Bocher V., Remaley A.T., Neve B., Torra I.P., Teissier E., Minnich A., Jaye M., Duverger N., Brewer H.B., Fruchart J.C., Clavey V., Staels B.: PPAR-a and PPAR-g activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med., 2001; 7: 53-58
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[41] Chu K., Miyazaki M., Man W.C., Ntambi JM.: Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation. Mol. Cell. Biol., 2006; 26: 6786-6798
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[42] Costet P., Luo Y., Wang N., Tall A.R.: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem., 2000; 275: 28240-28245
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[43] DeBose-Boyd R.A., Ou J., Goldstein J.L., Brown M.S.: Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc. Natl. Acad. Sci. USA, 2001; 98: 1477-1482
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[44] Duval C., Touche V., Tailleux A., Fruchart J.C., Fievet C., Clavey V., Staels B., Lestavel S.: Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine. Biochem. Biophys. Res. Commun., 2006; 340: 1259-1263
[PubMed]  
[45] Edwards P.A., Kennedy M.A., Mak P.A.: LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. Vascul. Pharmacol., 2002; 38: 249-256
[PubMed]  
[46] Engel T., Lorkowski S., Lueken A., Rust S., Schluter B., Berger G., Cullen P., Assmann G.: The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages. Biochem. Biophys. Res. Commun., 2001; 288: 483-488
[PubMed]  
[47] Fang C., Yoon S., Tindberg N., Jarvelainen H.A., Lindros K.O., Ingelman-Sundberg M.: Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure. Biochem. Pharmacol., 2004; 67: 1389-1397
[PubMed]  
[48] Field F.J., Born E., Mathur S.N.: LXR/RXR ligand activation enhances basolateral efflux of b-sitosterol in CaCo-2 cells. J. Lipid Res., 2004; 45: 905-913
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[49] Forcheron F., Cachefo A., Thevenon S., Pinteur C., Beylot M.: Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients. Diabetes, 2002; 51: 3486-3491
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[50] Forman B.M., Ruan B., Chen J., Schroepfer G.J. Jr., Evans R.M.: The orphan nuclear receptor LXRa is positively and negatively regulated by distinct products of mevalonate metabolism. Proc. Natl. Acad. Sci. USA, 1997; 94: 10588-10593
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[51] Fu X., Menke J.G., Chen Y., Zhou G., MacNaul K.L., Wright S.D., Sparrow C.P., Lund E.G.: 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J. Biol. Chem., 2001; 276: 38378-38387
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[52] Fujiyoshi M., Ohtsuki S., Hori S., Tachikawa M., Terasaki T.: 24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical- and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression. J. Neurochem., 2007; 100: 968-978
[PubMed]  
[53] Gan X., Kaplan R., Menke J.G., MacNaul K., Chen Y., Sparrow C.P., Zhou G., Wright S.D., Cai T.Q.: Dual mechanisms of ABCA1 regulation by geranylgeranyl pyrophosphate. J. Biol. Chem., 2001; 276: 48702-48708
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[54] Gbaguidi G.F., Agellon L.B.: The inhibition of the human cholesterol 7a-hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor a and peroxisome proliferator-activated receptor a heterodimer. Nucleic Acids Res., 2004; 32: 1113-1121
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[55] Goodwin B., Watson M.A., Kim H., Miao J., Kemper J.K., Kliewer S.A.: Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-a. Mol. Endocrinol., 2003; 17: 386-394
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[56] Grefhorst A., Elzinga B.M., Voshol P.J., Plosch T., Kok T., Bloks V.W., van der Sluijs F.H., Havekes L.M., Romijn J.A., Verkade H.J., Kuipers F.: Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J. Biol. Chem., 2002; 277: 34182-34190
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[57] Grefhorst A., van Dijk T.H., Hammer A., van der Sluijs F.H., Havinga R., Havekes L.M., Romijn J.A., Groot P.H., Reijngoud D.J., Kuipers F.: Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice. Am. J. Physiol. Endocrinol. Metab., 2005; 289: E829-E838
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[58] Groot P.H., Pearce N.J., Yates J.W., Stocker C., Sauermelch C., Doe C.P., Willette R.N., Olzinski A., Peters T., d'Epagnier D., Morasco K.O., Krawiec J.A., Webb C.L., Aravindhan K., Jucker B., Burgert M., Ma C., Marino J.P., Collins J.L., Macphee C.H., Thompson S.K., Jaye M.: Synthetic LXR agonists increase LDL in CETP species. J. Lipid Res., 2005; 46: 2182-2191
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[59] Hammarstedt A., Sopasakis V.R., Gogg S., Jansson P.A., Smith U.: Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects. Diabetologia, 2005; 48: 96-104
[PubMed]  
[60] Hashimoto K., Cohen R.N., Yamada M., Markan K.R., Monden T., Satoh T., Mori M., Wondisford F.E.: Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. J. Biol. Chem., 2006; 281: 295-302
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[61] Hegarty B.D., Bobard A., Hainault I., Ferre P., Bossard P., Foufelle F.: Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. Proc. Natl. Acad. Sci. USA, 2005; 102: 791-796
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[62] Hegele R.A., Robinson J.F.: ABC transporters and sterol absorption. Curr. Drug Targets Cardiovasc. Haematol. Disord., 2005; 5: 31-37
[PubMed]  
[63] Houck K.A., Borchert K.M., Hepler C.D., Thomas J.S., Bramlett K.S., Michael L.F., Burris T.P.: T0901317 is a dual LXR/FXR agonist. Mol. Genet. Metab., 2004; 83: 184-187
[PubMed]  
[64] Hu T., Foxworthy P., Siesky A., Ficorilli J.V., Gao H., Li S., Christe M., Ryan T., Cao G., Eacho P., Michael M.D., Michael L.F.: Hepatic peroxisomal fatty acid b-oxidation is regulated by liver X receptor a. Endocrinology, 2005; 146: 5380-5387
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[65] Hummasti S., Laffitte B.A., Watson M.A., Galardi C., Chao L.C., Ramamurthy L., Moore J.T., Tontonoz P.: Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target. J. Lipid Res., 2004; 45: 616-625
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[66] Ide T., Shimano H., Yoshikawa T., Yahagi N., Amemiya-Kudo M., Matsuzaka T., Nakakuki M., Yatoh S., Iizuka Y., Tomita S., Ohashi K., Takahashi A., Sone H., Gotoda T., Osuga J., Ishibashi S., Yamada N.: Cross-talk between peroxisome proliferator-activated receptor (PPAR) a and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol. Endocrinol., 2003; 17: 1255-1267
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[67] Ishimoto K., Tachibana K., Sumitomo M., Omote S., Hanano I., Yamasaki D., Watanabe Y., Tanaka T., Hamakubo T., Sakai J., Kodama T., Doi T.: Identification of human low-density lipoprotein receptor as a novel target gene regulated by liver X receptor a. FEBS Lett., 2006; 580: 4929-4933
[PubMed]  
[68] Jakel H., Nowak M., Moitrot E., Dehondt H., Hum D.W., Pennacchio L.A., Fruchart-Najib J., Fruchart J.C.: The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J. Biol. Chem., 2004; 279: 45462-45469
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[69] Janowski B.A., Grogan M.J., Jones S.A., Wisely G.B., Kliewer S.A., Corey E.J., Mangelsdorf D.J.: Structural requirements of ligands for the oxysterol liver X receptors LXRa and LXRb. Proc. Natl. Acad. Sci. USA, 1999; 96: 266-271
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[70] Janowski B.A., Willy P.J., Devi T.R., Falck J.R., Mangelsdorf D.J.: An oxysterol signalling pathway mediated by the nuclear receptor LXR a. Nature, 1996; 383: 728-731
[PubMed]  
[71] Jiang W., Miyamoto T., Kakizawa T., Nishio S.I., Oiwa A., Takeda T., Suzuki S., Hashizume K.: Inhibition of LXRa signaling by vitamin D receptor: possible role of VDR in bile acid synthesis. Biochem. Biophys. Res. Commun., 2006; 351: 176-184
[PubMed]  
[72] Jiang X.C., Beyer T.P., Li Z., Liu J., Quan W., Schmidt R.J., Zhang Y., Bensch W.R., Eacho P.I., Cao G.: Enlargement of high density lipoprotein in mice via liver X receptor activation requires apolipoprotein E and is abolished by cholesteryl ester transfer protein expression. J. Biol. Chem., 2003; 278: 49072-49078
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[73] Joseph S.B., Laffitte B.A., Patel P.H., Watson M.A., Matsukuma K.E., Walczak R., Collins J.L., Osborne T.F., Tontonoz P.: Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J. Biol. Chem., 2002; 277: 11019-11025
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[74] Juvet L.K., Andresen S.M., Schuster G.U., Dalen K.T., Tobin K.A., Hollung K., Haugen F., Jacinto S., Ulven S.M., Bamberg K., Gustafsson J.A., Nebb H.I.: On the role of liver X receptors in lipid accumulation in adipocytes. Mol. Endocrinol., 2003; 17: 172-182
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[75] Kaneko E., Matsuda M., Yamada Y., Tachibana Y., Shimomura I., Makishima M.: Induction of intestinal ATP-binding cassette transporters by a phytosterol-derived liver X receptor agonist. J. Biol. Chem., 2003; 278: 36091-36098
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[76] Kawai K., Sasaki S., Morita H., Ito T., Suzuki S., Misawa H., Nakamura H.: Unliganded thyroid hormone receptor-b1 represses liver X receptor a/oxysterol-dependent transactivation. Endocrinology, 2004; 145: 5515-5524
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[77] Kennedy M.A., Barrera G.C., Nakamura K., Baldan A., Tarr P., Fishbein M.C., Frank J., Francone O.L., Edwards P.A.: ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab., 2005; 1: 121-131
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[78] Kennedy M.A., Venkateswaran A., Tarr P.T., Xenarios I., Kudoh J., Shimizu N., Edwards P.A.: Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem., 2001; 276: 39438-39447
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[79] Khovidhunkit W., Moser A.H., Shigenaga J.K., Grunfeld C., Feingold K.R.: Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. J. Lipid Res., 2003; 44: 1728-1736
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[80] Kim M.S., Sweeney T.R., Shigenaga J.K., Chui L.G., Moser A., Grunfeld C., Feingold K.R.: Tumor necrosis factor and interleukin 1 decrease RXRa, PPARa, PPARg, LXRa, and the coactivators SRC-1, PGC-1a, and PGC-1b in liver cells. Metabolism, 2007; 56: 267-279
[PubMed]  
[81] Kiss L., Chen M., Gero D., Modis K., Lacza Z., Szabo C.: Effects of 7-ketocholesterol on the activity of endothelial poly(ADP-ribose) polymerase and on endothelium-dependent elaxant function. Int. J. Mol. Med., 2006; 18: 1113-1117
[PubMed]  
[82] Klerkx A.H., El Harchaoui K., van der Steeg W.A., Boekholdt S.M., Stroes E.S., Kastelein J.J., Kuivenhoven J.A.: Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels: pathways by which modulation of CETP activity may alter atherogenesis. Arterioscler. Thromb. Vasc. Biol., 2006; 26: 706-715
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[83] Kotti T.J., Ramirez D.M., Pfeiffer B.E., Huber K.M., Russell D.W.: Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc. Natl. Acad. Sci. USA, 2006; 103: 3869-3874
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[84] Kramer P.R., Wray S.: 17b-estradiol regulates expression of genes that function in macrophage activation and cholesterol homeostasis. J. Steroid Biochem. Mol. Biol., 2002; 81: 203-216
[PubMed]  
[85] Kruit J.K., Plosch T., Havinga R., Boverhof R., Groot P.H., Groen A.K., Kuipers F.: Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Gastroenterology, 2005; 128: 147-156
[PubMed]  
[86] Kuliszkiewicz-Janus M., Mohamed A.S., Abod N.: Biologia lipoproteiny HDL i jej przeciwmiażdżycowe działanie. Post. Hig. Med. Dośw., 2006; 60: 307-315
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[87] Laffitte B.A., Joseph S.B., Chen M., Castrillo A., Repa J., Wilpitz D., Mangelsdorf D., Tontonoz P.: The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol. Cell. Biol., 2003; 23: 2182-2191
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[88] Laffitte B.A., Joseph S.B., Walczak R., Pei L., Wilpitz D.C., Collins J.L., Tontonoz P.: Autoregulation of the human liver X receptor a promoter. Mol. Cell. Biol., 2001; 21: 7558-7568
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[89] Laffitte B.A., Repa J.J., Joseph S.B., Wilpitz D.C., Kast H.R., Mangelsdorf D.J., Tontonoz P.: LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. USA, 2001; 98: 507-512
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[90] Landrier J.F., Grober J., Demydchuk J., Besnard P.: FXRE can function as an LXRE in the promoter of human ileal bile acid-binding protein (I-BABP) gene. FEBS Lett., 2003; 553: 299-303
[PubMed]  
[91] Larsson D.A., Baird S., Nyhalah J.D., Yuan X.M., Li W.: Oxysterol mixtures, in atheroma-relevant proportions, display synergistic and proapoptotic effects. Free Radic. Biol. Med., 2006; 41: 902-910
[PubMed]  
[92] Lehmann J.M., Kliewer S.A., Moore L.B., Smith-Oliver T.A., Oliver B.B., Su J.L., Sundseth S.S., Winegar D.A., Blanchard D.E., Spencer T.A., Willson T.M.: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem., 1997; 272: 3137-3140
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[93] Li Y., Bolten C., Bhat B.G., Woodring-Dietz J., Li S., Prayaga S.K., Xia C., Lala D.S.: Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. Mol. Endocrinol., 2002; 16: 506-514
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[94] Liao H., Langmann T., Schmitz G., Zhu Y.: Native LDL upregulation of ATP-binding cassette transporter-1 in human vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol., 2002; 22: 127-132
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[95] Li-Hawkins J., Lund E.G., Bronson A.D., Russell D.W.: Expression cloning of an oxysterol 7a-hydroxylase selective for 24-hydroxycholesterol. J. Biol. Chem., 2000; 275: 16543-16549
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[96] Lin Y.Y., Smith L.L.: Sterol metabolism. 28. Biosynthesis and accumulation of cholest-5-ene-3beta, 24-diol (cerebrosterol) in developing rat brain. Biochim. Biophys. Acta, 1974; 348: 189-196
[PubMed]  
[97] Lu B., Moser A.H., Shigenaga J.K., Feingold K.R., Grunfeld C.: Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response. J. Lipid Res.,2006; 47: 2179-2190
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[98] Lund E., Andersson O., Zhang J., Babiker A., Ahlborg G., Diczfalusy U., Einarsson K., Sjovall J., Bjorkhem I.: Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans. Arterioscler. Thromb. Vasc. Biol., 1996; 16: 208-212
[PubMed]  [Full Text HTML]  
[99] Lund E.G., Kerr T.A., Sakai J., Li W.P., Russell D.W.: cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J. Biol. Chem., 1998; 273: 34316-34327
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[100] Lundholm L., Moverare S., Steffensen K.R., Nilsson M., Otsuki M., Ohlsson C., Gustafsson J.A., Dahlman-Wright K.: Gene expression profiling identifies liver X receptor a as an estrogen-regulated gene in mouse adipose tissue. J. Mol. Endocrinol., 2004; 32: 879-892
[PubMed]  [Full Text PDF]  
[101] Luo Y., Tall A.R.: Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J. Clin. Invest., 2000; 105: 513-520
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[102] Lutjohann D., Breuer O., Ahlborg G., Nennesmo I., Siden A., Diczfalusy U., Bjorkhem I.: Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc. Natl. Acad. Sci. USA, 1996; 93: 9799-9804
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[103] Mak P.A., Kast-Woelbern H.R., Anisfeld A.M., Edwards P.A.: Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J. Lipid Res., 2002; 43: 2037-2041
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[104] Mak P.A., Laffitte B.A., Desrumaux C., Joseph S.B., Curtiss L.K., Mangelsdorf D.J., Tontonoz P., Edwards P.A.: Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors a and b. J. Biol. Chem., 2002; 277: 31900-31908
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[105] Makishima M., Lu T.T., Xie W., Whitfield G.K., Domoto H., Evans R.M., Haussler M.R., Mangelsdorf D.J.: Vitamin D receptor as an intestinal bile acid sensor. Science, 2002; 296: 1313-1316
[PubMed]  
[106] Malerod L., Juvet L.K., Hanssen-Bauer A., Eskild W., Berg T.: Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem. Biophys. Res. Commun., 2002; 299: 916-923
[PubMed]  
[107] Marcil V., Delvin E., Sane A.T., Tremblay A., Levy E.: Oxidative stress influences cholesterol efflux in THP-1 macrophages: role of ATP-binding cassette A1 and nuclear factors. Cardiovasc. Res., 2006; 72: 473-482
[PubMed]  
[108] Martinet W., De Bie M., Schrijvers D.M., De Meyer G.R., Herman A.G., Kockx M.M.: 7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 2004; 24: 2296-2301
[PubMed]  
[109] Masson D., Staels B., Gautier T., Desrumaux C., Athias A., Le Guern N., Schneider M., Zak Z., Dumont L., Deckert V., Tall A., Jiang X.C., Lagrost L.: Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse. J. Lipid Res., 2004; 45: 543-550
[PubMed]  
[110] Matsusue K., Miyoshi A., Yamano S., Gonzalez F.J.: Ligand-activated PPARb efficiently represses the induction of LXR-dependent promoter activity through competition with RXR. Mol. Cell. Endocrinol., 2006; 256: 23-33
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[111] Menke J.G., Macnaul K.L., Hayes N.S., Baffic J., Chao Y.S., Elbrecht A., Kelly L.J., Lam M.H., Schmidt A., Sahoo S., Wang J., Wright S.D., Xin P., Zhou G., Moller D.E., Sparrow C.P.: A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7a-hydroxylase (CYP7a). Endocrinology, 2002; 143: 2548-2558
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[112] Mitro N., Mak P.A., Vargas L., Godio C., Hampton E., Molteni V., Kreusch A., Saez E.: The nuclear receptor LXR is a glucose sensor. Nature. 2007; 445: 219-223
[PubMed]  
[113] Miyata K.S., McCaw S.E., Patel H.V., Rachubinski R.A., Capone J.P.: The orphan nuclear hormone receptor LXR a interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J. Biol. Chem., 1996; 271: 9189-9192
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[114] Mo J., Fang S.J., Chen W., Blobe G.C.: Regulation of ALK-1 signaling by the nuclear receptor LXRb. J. Biol. Chem., 2002; 277: 50788-50794
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[115] Moriishi K., Mochizuki R., Moriya K., Miyamoto H., Mori Y., Abe T., Murata S., Tanaka K., Miyamura T., Suzuki T., Koike K., Matsuura Y.: Critical role of PA28g in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc. Natl. Acad. Sci. USA, 2007; 104: 1661-1666
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[116] Murthy S., Born E., Mathur S.N., Field F.J.: LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells. J. Lipid Res., 2002; 43: 1054-1064
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[117] Naik S.U., Wang X., Da Silva J.S., Jaye M., Macphee C.H., Reilly M.P., Billheimer J.T., Rothblat G.H., Rader D.J.: Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation, 2006; 113: 90-97
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[118] Neumeier M., Weigert J., Schaffler A., Weiss T., Kirchner S., Laberer S., Scholmerich J., Buechler C.: Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors. Biochem. Biophys. Res. Commun., 2005; 334: 924-929
[PubMed]  
[119] Norata G.D., Ongari M., Uboldi P., Pellegatta F., Catapano A.L.: Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells. Int. J. Mol. Med., 2005; 16: 717-722
[PubMed]  
[120] Norlin M., Toll A., Bjorkhem I., Wikvall K.: 24-hydroxycholesterol is a substrate for hepatic cholesterol 7a-hydroxylase (CYP7A). J. Lipid Res., 2000; 41: 1629-1639
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[121] Ohama T., Hirano K., Zhang Z., Aoki R., Tsujii K., Nakagawa-Toyama Y., Tsukamoto K., Ikegami C., Matsuyama A., Ishigami M., Sakai N., Hiraoka H., Ueda K., Yamashita S., Matsuzawa Y.: Dominant expression of ATP-binding cassette transporter-1 on basolateral surface of Caco-2 cells stimulated by LXR/RXR ligands. Biochem. Biophys. Res. Commun., 2002; 296: 625-630
[PubMed]  
[122] Ou J., Tu H., Shan B., Luk A., DeBose-Boyd R.A., Bashmakov Y., Goldstein J.L., Brown M.S.: Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc. Natl. Acad. Sci. USA, 2001; 98: 6027-6032
[PubMed]  [Full Text PDF]  
[123] Panzenboeck U., Kratzer I., Sovic A., Wintersperger A., Bernhart E., Hammer A., Malle E., Sattler W.: Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells. Int. J. Biochem. Cell Biol., 2006; 38: 1314-1329
[PubMed]  
[124] Patel M.D., Thompson P.D.: Phytosterols and vascular disease. Atherosclerosis, 2006; 186: 12-19
[PubMed]  
[125] Pedruzzi E., Guichard C., Ollivier V., Driss F., Fay M., Prunet C., Marie J.C., Pouzet C., Samadi M., Elbim C., O'dowd Y., Bens M., Vandewalle A., Gougerot-Pocidalo M.A., Lizard G., Ogier-Denis E.: NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol. Cell. Biol., 2004; 24: 10703-10717
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[126] Peet D.J., Turley S.D., Ma W., Janowski B.A., Lobaccaro J.M., Hammer R.E., Mangelsdorf D.J.: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRa. Cell, 1998; 93: 693-704
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[127] Pikuleva I.A.: Cytochrome P450s and cholesterol homeostasis. Pharmacol. Ther., 2006; 112: 761-773
[PubMed]  
[128] Plat J., Nichols J.A., Mensink R.P.: Plant sterols and stanols: effects on mixed micellar composition and LXR (target gene) activation. J. Lipid Res., 2005; 46: 2468-2476
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[129] Plosch T., Bloks V.W., Terasawa Y., Berdy S., Siegler K., Van Der Sluijs F., Kema I.P., Groen A.K., Shan B., Kuipers F., Schwarz M.: Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor. Gastroenterology, 2004; 126: 290-300
[PubMed]  
[130] Plosch T., Kok T., Bloks V.W., Smit M.J., Havinga R., Chimini G., Groen A.K., Kuipers F.: Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J. Biol. Chem., 2002; 277: 33870-33877
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[131] Porkkala-Sarataho E., Salonen J.T., Nyyssonen K., Kaikkonen J., Salonen R., Ristonmaa U., Diczfalusy U., Brigelius-Flohe R., Loft S., Poulsen H.E.: Long-term effects of vitamin E, vitamin C, and combined supplementation on urinary 7-hydro-8-oxo-2'-deoxyguanosine, serum cholesterol oxidation products, and oxidation resistance of lipids in nondepleted men. Arterioscler. Thromb. Vasc. Biol., 2000; 20: 2087-2093
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[132] Recalde D., Ostos M.A., Badell E., Garcia-Otin A.L., Pidoux J., Castro G., Zakin M.M., Scott-Algara D.: Human apolipoprotein A-IV reduces secretion of proinflammatory cytokines and atherosclerotic effects of a chronic infection mimicked by lipopolysaccharide. Arterioscler Thromb Vasc Biol., 2004; 24: 756-761
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[133] Rensen P.C., van Dijk K.W., Havekes L.M.: Apolipoprotein AV: low concentration, high impact. Arterioscler. Thromb. Vasc. Biol., 2005; 25: 2445-2447
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[134] Repa J.J., Berge K.E., Pomajzl C., Richardson J.A., Hobbs H., Mangelsdorf D.J.: Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors a and b. J. Biol. Chem. 2002; 277: 18793-18800
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[135] Repa J.J., Liang G., Ou J., Bashmakov Y., Lobaccaro J.M., Shimomura I., Shan B., Brown M.S., Goldstein J.L., Mangelsdorf D.J.: Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRa and LXRb. Genes Dev., 2000; 14: 2819-2830
[PubMed]  [Full Text HTML]  
[136] Repa J.J., Mangelsdorf D.J.: The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu. Rev. Cell Dev. Biol., 2000; 16: 459-481
[PubMed]  
[137] Repa J.J., Turley S.D., Lobaccaro J.A., Medina J., Li L., Lustig K., Shan B., Heyman R.A., Dietschy J.M., Mangelsdorf D.J.: Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science, 2000; 289: 1524-1529
[PubMed]  
[138] Rigamonti E., Helin L., Lestavel S., Mutka A.L., Lepore M., Fontaine C., Bouhlel M.A., Bultel S., Fruchart J.C., Ikonen E., Clavey V., Staels B., Chinetti-Gbaguidi G.: Liver X receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages. Circ. Res., 2005; 97: 682-689
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[139] Sabol S.L., Brewer H.B. Jr., Santamarina-Fojo S.: The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver. J. Lipid Res., 2005; 46: 2151-2167
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[140] Salonen J.T., Nyyssonen K., Salonen R., Porkkala-Sarataho E., Tuomainen T.P., Diczfalusy U., Bjorkhem I.: Lipoprotein oxidation and progression of carotid atherosclerosis. Circulation, 1997; 95: 840-845
[PubMed]  [Full Text HTML]  
[141] Schmidt A., Vogel R., Rutledge S.J., Opas E.E., Rodan G.A., Friedman E.: Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway. Pharmacol. Biochem. Behav., 2005; 80: 379-385
[PubMed]  
[142] Schultz J.R., Tu H., Luk A., Repa J.J., Medina J.C., Li L., Schwendner S., Wang S., Thoolen M., Mangelsdorf D.J., Lustig K.D., Shan B.: Role of LXRs in control of lipogenesis. Genes Dev., 2000; 14: 2831-2838
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[143] Seo J.B., Moon H.M., Kim W.S., Lee Y.S., Jeong H.W., Yoo E.J., Ham J., Kang H., Park M.G., Steffensen K.R., Stulnig T.M., Gustafsson J.A., Park S.D., Kim J.B.: Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor g expression. Mol. Cell. Biol., 2004; 24: 3430-3444
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[144] Shang Q., Pan L., Saumoy M., Chiang J.Y., Tint G.S., Salen G., Xu G.: The stimulatory effect of LXRa is blocked by SHP despite the presence of a LXRa binding site in the rabbit CYP7A1 promoter. J Lipid Res., 2006; 47: 997-1004
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[145] Shenoy S.D., Spencer T.A., Mercer-Haines N.A., Alipour M., Gargano M.D., Runge-Morris M., Kocarek T.A.: CYP3A induction by liver X receptor ligands in primary cultured rat and mouse hepatocytes is mediated by the pregnane X receptor. Drug Metab. Dispos., 2004; 32: 66-71
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[146] Shiffman D., Mikita T., Tai J.T., Wade D.P., Porter J.G., Seilhamer J.J., Somogyi R., Liang S., Lawn R.M.: Large scale gene expression analysis of cholesterol-loaded macrophages. J. Biol. Chem., 2000; 275: 37324-37332
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[147] Singh S.B., Ondeyka J.G., Liu W., Chen S., Chen T.S., Li X., Bouffard A., Dropinski J., Jones A.B., McCormick S., Hayes N., Wang J., Sharma N., Macnaul K., Hernandez M., Chao Y.S., Baffic J., Lam M.H., Burton C., Sparrow C.P., Menke J.G.: Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters. Bioorg. Med. Chem. Lett., 2005; 15: 2824-2828
[PubMed]  
[148] Skoczyńska A.: Rola lipidów w powstawaniu miażdżycy. Post. Hig. Med. Dośw., 2005; 59: 346-357
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[149] Song C., Hiipakka R.A., Liao S.: Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids, 2001; 66: 473-479
[PubMed]  
[150] Song C., Hiipakka R.A., Liao S.: Selective activation of liver X receptor a by 6a-hydroxy bile acids and analogs. Steroids, 2000; 65: 423-427
[PubMed]  
[151] Song C., Liao S.: Cholestenoic acid is a naturally occurring ligand for liver X receptor a. Endocrinology, 2000; 141: 4180-4184
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[152] Sovic A., Panzenboeck U., Wintersperger A., Kratzer I., Hammer A., Levak-Frank S., Frank S., Rader D.J., Malle E., Sattler W.: Regulated expression of endothelial lipase by porcine brain capillary endothelial cells constituting the blood-brain barrier. J. Neurochem., 2005; 94: 109-119
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[153] Sparrow C.P., Baffic J., Lam M.H., Lund E.G., Adams A.D., Fu X., Hayes N., Jones A.B., Macnaul K.L., Ondeyka J., Singh S., Wang J., Zhou G., Moller D.E., Wright S.D., Menke J.G.: A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J. Biol. Chem., 2002; 277: 10021-10027
[PubMed]  
[154] Stan S., Delvin E., Lambert M., Seidman E., Levy E.: Apo A-IV: an update on regulation and physiologic functions. Biochim. Biophys. Acta, 2003; 1631: 177-187
[PubMed]  
[155] Talukdar S., Hillgartner F.B.: The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. J. Lipid Res., 2006; 47: 2451-2461
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[156] Tamehiro N., Sato Y., Suzuki T., Hashimoto T., Asakawa Y., Yokoyama S., Kawanishi T., Ohno Y., Inoue K., Nagao T., Nishimaki-Mogami T.: Riccardin C: a natural product that functions as a liver X receptor (LXR)a agonist and an LXRb antagonist. FEBS Lett., 2005; 579: 5299-5304
[PubMed]  
[157] Tamura K., Chen Y.E., Horiuchi M., Chen Q., Daviet L., Yang Z., Lopez-Ilasaca M., Mu H., Pratt R.E., Dzau V.J.: LXRa functions as a cAMP-responsive transcriptional regulator of gene expression. Proc. Natl. Acad. Sci. USA, 2000; 97: 8513-8518
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[158] Tamura K., Chen Y.E., Tanaka Y., Sakai M., Tsurumi Y., Koide Y., Kihara M., Pratt R.E., Horiuchi M., Umemura S., Dzau V.J.: Nuclear receptor LXRa is involved in cAMP-mediated human renin gene expression. Mol. Cell. Endocrinol., 2004; 224: 11-20
[PubMed]  
[159] Tobin K.A., Steineger H.H., Alberti S., Spydevold O., Auwerx J., Gustafsson J.A., Nebb H.I.: Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-a. Mol. Endocrinol., 2000; 14: 741-752
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[160] Tobin K.A., Ulven S.M., Schuster G.U., Steineger H.H., Andresen S.M., Gustafsson J.A., Nebb H.I.: Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J. Biol. Chem., 2002; 277: 10691-10697
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[161] Ulven S.M., Dalen K.T., Gustafsson J.A., Nebb H.I.: Tissue-specific autoregulation of the LXRa gene facilitates induction of apoE in mouse adipose tissue. J. Lipid Res., 2004; 45: 2052-2062
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[162] Venkateswaran A., Repa J.J., Lobaccaro J.M., Bronson A., Mangelsdorf D.J. Edwards P.A.: Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J. Biol. Chem., 2000; 275: 14700-14707
[PubMed]  
[163] Verreault M., Senekeo-Effenberger K., Trottier J., Bonzo J.A., Belanger J., Kaeding J., Staels B., Caron P., Tukey R.H., Barbier O.: The liver X-receptor ? controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice. Hepatology, 2006; 44: 368-378
[PubMed]  
[164] von Bahr S., Movin T., Papadogiannakis N., Pikuleva I., Ronnow P., Diczfalusy U., Bjorkhem I.: Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1). Arterioscler. Thromb. Vasc. Biol., 2002; 22: 1129-1135
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[165] Wang D.Q.: Regulation of intestinal cholesterol absorption. Annu. Rev. Physiol., 2007; 69: 221-248
[PubMed]  
[166] Wang M.D., Kiss R.S., Franklin V., McBride H.M., Whitman S.C., Marcel Y.L.: Different intracellular trafficking of LDL- and acetylated LDL-derived cholesterol lead to distinct reverse cholesterol transport mechanisms. J. Lipid Res., 2007; 48: 633-645
[PubMed]  
[167] Wang N., Ranalletta M., Matsuura F., Peng F., Tall A.R.: LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Arterioscler. Thromb. Vasc. Biol., 2006; 26: 1310-1316
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[168] Wang Y., Kurdi-Haidar B., Oram J.F.: LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J. Lipid Res., 2004; 45: 972-980
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[169] Wang Y., Moser A.H., Shigenaga J.K., Grunfeld C., Feingold K.R.: Downregulation of liver X receptor-a in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines. J. Lipid Res., 2005; 46: 2377-2387
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[170] Whitney K.D., Watson M.A., Goodwin B., Galardi C.M., Maglich J.M., Wilson J.G., Willson T.M., Collins J.L., Kliewer S.A.: Liver X receptor (LXR) regulation of the LXRa gene in human macrophages. J. Biol. Chem., 2001; 276: 43509-43515
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[171] Willy P.J., Umesono K., Ong E.S., Evans R.M., Heyman R.A., Mangelsdorf D.J.: LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev., 1995; 9: 1033-1045
[PubMed]  [Full Text PDF]  
[172] Wu J., Zhang Y., Wang N., Davis L., Yang G., Wang X., Zhu Y., Breyer M.D., Guan Y.: Liver X receptor-a mediates cholesterol efflux in glomerular mesangial cells. Am. J. Physiol. Renal. Physiol., 2004; 287: F886-F895
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[173] Xu G., Li H., Pan L.X., Shang Q., Honda A., Ananthanarayanan M., Erickson S.K., Shneider B.L., Shefer S., Bollineni J., Forman B.M., Matsuzaki Y., Suchy F.J., Tint G.S., Salen G.: FXR-mediated down-regulation of CYP7A1 dominates LXRa in long-term cholesterol-fed NZW rabbits. J. Lipid Res., 2003; 44: 1956-1962
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[174] Xu G., Pan L.X., Li H., Shang Q., Honda A., Shefer S., Bollineni J., Matsuzaki Y., Tint G.S., Salen G.: Dietary cholesterol stimulates CYP7A1 in rats because farnesoid X receptor is not activated. Am. J. Physiol. Gastrointest. Liver Physiol., 2004; 286: G730-G735
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[175] Yamamoto T., Shimano H., Inoue N., Nakagawa Y., Matsuzaka T., Takahashi A., Yahagi N., Sone H., Suzuki H., Toyoshima H., Yamada N.: Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver. J Biol Chem., 2007; 282: 11687-11695
[PubMed]  
[176] Yang C., McDonald J.G., Patel A., Zhang Y., Umetani M., Xu F., Westover E.J., Covey D.F., Mangelsdorf D.J., Cohen J.C., Hobbs H.H.: Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J. Biol. Chem., 2006; 281: 27816-27826
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[177] Yang C., Yu L., Li W., Xu F., Cohen J.C., Hobbs H.H.: Disruption of cholesterol homeostasis by plant sterols. J. Clin. Invest., 2004; 114: 813-822
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[178] Yoshikawa T., Ide T., Shimano H., Yahagi N., Amemiya-Kudo M., Matsuzaka T., Yatoh S., Kitamine T., Okazaki H., Tamura Y., Sekiya M., Takahashi A., Hasty A.H., Sato R., Sone H., Osuga J., Ishibashi S., Yamada N.: Cross-talk between peroxisome proliferator-activated receptor (PPAR) a and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol. Endocrinol., 2003; 17: 1240-1254
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[179] Yoshikawa T., Shimano H., Amemiya-Kudo M., Yahagi N., Hasty A.H., Matsuzaka T., Okazaki H., Tamura Y., Iizuka Y., Ohashi K., Osuga J., Harada K., Gotoda T., Kimura S., Ishibashi S., Yamada N.: Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol. Cell. Biol., 2001; 21: 2991-3000
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[180] Yoshikawa T., Shimano H., Yahagi N., Ide T., Amemiya-Kudo M., Matsuzaka T., Nakakuki M., Tomita S., Okazaki H., Tamura Y., Iizuka Y., Ohashi K., Takahashi A., Sone H., Osuga Ji J., Gotoda T., Ishibashi S., Yamada N.: Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J. Biol. Chem., 2002; 277: 1705-1711
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[181] Yu L., Cao G., Repa J., Stangl H.: Sterol regulation of scavenger receptor class B type I in macrophages. J. Lipid Res., 2004; 45: 889-899
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[182] Yu L., York J., von Bergmann K., Lutjohann D., Cohen J.C., Hobbs H.H.: Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J. Biol. Chem., 2003; 278: 15565-15570
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[183] Zhang Y., Repa J.J., Gauthier K., Mangelsdorf D.J.: Regulation of lipoprotein lipase by the oxysterol receptors, LXRa and LXRb. J. Biol. Chem., 2001; 276: 43018-43024
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[184] Zhang Y., Repa J.J., Inoue Y., Hayhurst G.P., Gonzalez F.J., Mangelsdorf D.J.: Identification of a liver-specific uridine phosphorylase that is regulated by multiple lipid-sensing nuclear receptors. Mol. Endocrinol., 2004; 18: 851-862
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[185] Zhang Y., Zhang X., Chen L., Wu J., Su D., Lu W.J., Hwang M.T., Yang G., Li S., Wei M., Davis L., Breyer M.D., Guan Y.: Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule. Am. J. Physiol. Renal Physiol., 2006; 290: F1065-F1073
[PubMed]  [Full Text HTML]  [Full Text PDF]  
[186] Zhu Y., Liao H., Xie X., Yuan Y., Lee T.S., Wang N., Wang X., Shyy J.Y., Stemerman M.B.: Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR). Cardiovasc. Res., 2005; 68: 425-432
[PubMed]