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Liver X Receptor Signaling Pathways in Cardiovascular Disease

Howard Hughes Medical Institute (P.T., D.J.M.), Department of Pathology and Laboratory Medicine (P.T.), University of California, Los Angeles, California 90095-1662; and Department of Pharmacology (D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050

Address all correspondence and requests for reprints to: Peter Tontonoz, M.D., Ph.D., Howard Hughes Medical Institute, University of California, Los Angeles School of Medicine, Box 951662, Los Angeles, California 90095-1662. E-mail: ptontonoz{at}mednet.ucla.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
The liver X receptors and ß (LXR and LXRß) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport, and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
ATHEROSCLEROSIS IS THE leading cause of mortality in developed countries, accounting for nearly 50% of all deaths. Both environmental and genetic factors contribute to the development of atherosclerosis. Epidemiological studies have identified high levels of low-density lipoprotein (LDL) cholesterol and decreased levels of high-density lipoprotein (HDL) cholesterol as major contributors to atherogenesis (1, 2). As a result, many current therapies for the treatment of atherosclerosis, notably the statin class of lipid-lowering drugs, are aimed at lowering plasma LDL cholesterol. Statins are not a cure, however, and the development of additional agents is needed. Attractive therapeutic strategies for intervention in cardiovascular disease include elevation of plasma HDL levels and reduction of vascular inflammation. Drugs that accomplish one or both of these goals may represent the future of cardiovascular medicine.

A particularly attractive point for intervention in atherosclerosis is the so-called reverse cholesterol transport pathway (3). In this process, HDL carries cholesterol from peripheral tissues to the liver, where it can be secreted directly into bile or converted to bile acids. Although the atheroprotective effects of elevated HDL levels are likely to involve multiple mechanisms, the importance of HDL in reverse cholesterol transport is thought to be a major contributor. Several lines of evidence indicate that reverse cholesterol transport is important for removing cholesterol from the actual site of atherogenesis in the vasculature. In the setting of hypercholesterolemia, macrophages in the artery wall accumulate large amounts of cholesterol ester derived from the scavenging of oxidized LDL cholesterol (1, 2). Although some can be converted to 27-hydroxycholesterol, cells rid themselves of most of this free cholesterol through efflux to acceptor apolipoproteins (Apos), such as ApoAI and ApoE. The resulting pre-HDL particle is subsequently converted to HDL and transported to the liver, where it is taken up by scavenger receptor type BI (SR-BI). The elucidation of the molecular mechanisms involved in reverse cholesterol transport has led to the identification of new targets for raising HDL levels and limiting the development of cardiovascular disease. This review will focus on two potential targets, the nuclear receptors LXR and LXRß.

	LXRs: NUCLEAR RECEPTORS AS CHOLESTEROL SENSORS

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
Considerable evidence indicates that LXRs function as whole body cholesterol sensors. Consistent with this physiological role, the endogenous ligands for LXRs are likely to be intermediates or end products of sterol metabolic pathways. Both LXR and LXRß are activated by physiological concentrations of sterol metabolites such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, and 24(S), 25-epoxycholesterol (4, 5, 6). The two LXRs share considerable sequence homology and appear to respond to the same endogenous ligands. Their tissue distribution differs, however. LXR is highly expressed at in liver, adipose tissue, and macrophages, whereas LXRß is expressed in all tissues examined (7). Similar to other members of the nuclear receptor family, these proteins contain a zinc finger DNA-binding domain and a ligand-binding domain that accommodates specific small lipophilic molecules. Ligand binding triggers a conformational change that promotes interaction with coactivator proteins and facilitates the activation of specific target genes. LXRs bind to their target DNA sequences in heterodimeric complexes with the retinoid X receptor (RXR) (8). LXR/RXR is a so-called permissive heterodimer, in that it can be activated by ligands for either LXR or RXR.

Mice carrying targeted disruption of the LXR genes have been invaluable tools for the dissection of LXR biology (9, 10). The first LXR target to be identified was CYP7A1, the enzyme that catalyzes the rate-limiting step in bile acid synthesis. The inability of LXR null mice to appropriately regulate this gene provided the first clue to function of LXRs in cholesterol metabolism (10). On a high-cholesterol diet, LXR null mice exhibit dramatically increased plasma LDL cholesterol and decreased HDL cholesterol levels. Conversely, administration of a synthetic LXR agonist to a mouse receiving no dietary cholesterol results in a substantial increase in the fecal excretion of neutral sterols (11). Cholesterol loss in the mouse also results in part from an increase in conversion to bile acids due to enhanced expression and activity of the CYP7A1 gene. LXR agonists would not be expected to promote bile acid synthesis in humans, however, as the LXR response element is not conserved in the promoter of the human CYP7A1 gene (12).

Since the discovery of CYP7A1, an array of additional LXRs targets has been identified. Not surprisingly, many of these genes have clear links to lipid metabolism (schematized in Fig. 1). Characterization of these new LXR targets has expanded our understanding of the role of LXRs in lipid homeostasis and has fueled speculation as to how regulation of these genes by LXR ligands might impact the development of atherosclerosis. Below, we review a number of recently characterized LXR target genes and discuss their potential physiological and pathophysiological relevance. We also discuss recent in vivo studies that directly link the LXR signaling pathway to the development of cardiovascular disease.

View larger version (36K): [in this window] [in a new window]   Figure 1. The Role of LXR Target Genes in Cholesterol Homeostasis and Lipogenesis LXR target genes are indicated by boxes. C, Cholesterol; TG, triglyceride.

	ATP BINDING CASSETTE (ABC) TRANSPORTERS

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

Multiple studies have established the central role of LXRs in the control of ABCA1 expression and cholesterol efflux (13, 23, 24, 25). Repa et al. (13) established that LXR/RXR heterodimers are key regulators of ABCA1 expression in vivo and showed that ligand activation of LXR inhibits intestinal cholesterol absorption. They also showed that the ability of oxysterol and synthetic LXR activators to stimulate ABCA1 expression is lost in mice lacking LXRs. Costet et al. (23) identified an LXR response element in the promoter of the ABCA1 gene. Venkateswaran et al. and Schwartz et al. (24, 25) demonstrated that ABCA1 mRNA expression is induced in macrophages in response to lipid loading and that expression and activation of LXR stimulates ApoA-I mediated efflux of cholesterol. Importantly, the ability of LXR to stimulate cholesterol efflux is directly related to its ability to control ABCA1 because the effect of LXR ligands is lost in fibroblasts from Tangier patients. The ability of LXR ligands to raise HDL cholesterol levels in mice is consistent with the established function of ABCA1 in reverse cholesterol transport (14). Finally, LXRß null mice develop splenomegaly and accumulate foam cells in multiple peripheral tissues, a phenotype remarkably similar to that of the ABCA1 null mice (26, 27).

Several other ABC transporters have also been identified as LXR targets, including ABCG1, ABCG5, and ABCG8. Similar to ABCA1, expression of ABCG1 is also induced in macrophages in response to cholesterol loading and specific oxysterol LXR ligands (28). The function of ABCG1 is currently unknown, but it has been proposed to play a role in cholesterol efflux, perhaps by working in concert with ABCA1 (29). ABCG5 and ABCG8 were recently identified as the genes responsible another rare genetic disorder, sitosterolemia (30, 31). Patients with this disease exhibit hyperabsorption of cholesterol and show an abnormal capacity to absorb plant sterols from their diet. Patients also show diminished secretion of sterols into bile and hypercholesterolemia and develop premature cardiovascular disease. The ABCG5 and ABCG8 proteins form a dimer that resides in the apical membrane of the hepatocyte and functions to pump cholesterol into bile. Initial studies postulated that ABCA1 may be the key target responsible for LXR inhibition of cholesterol absorption; however, recent studies suggest that ABCG5 and ABCG8 may play a more prominent role in this effect (32, 33). ABCG5 and ABCG8 expression is enhanced by LXR agonists in mice in a receptor-dependent manner (34). In accordance with these changes, biliary cholesterol content is increased and cholesterol absorption efficiency is decreased (13, 35). Similar changes have been observed in transgenic mice overexpressing the human ABCG5 and ABCG8 genes (36). Finally, the ability of LXR ligands to stimulate biliary cholesterol secretion is preserved in mice lacking ABCA1, consistent with an important role for ABCG5 and ABCG8 in this process (35).

	APOLIPOPROTEINS

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ApoE is a principal protein component of chylomicron remnants, very low-density lipoproteins (VLDLs) and intermediate-density lipoproteins. Recognition of ApoE by LDL receptors mediates hepatic uptake of these particles (37). In addition to the liver, ApoE is expressed by a number of peripheral tissues and cell types, including adipose tissue, macrophages, and the brain. Hepatic ApoE expression is controlled by a distal enhancer known as the hepatic control region, whereas expression in macrophages and adipocytes is directed by a distinct flanking sequence termed the multiple enhancer (ME) region (38). ApoE was the first gene shown to be regulated by LXR/RXR heterodimers in a tissue-specific manner (39). LXR mediates lipid-inducible expression of the ApoE gene in adipose tissue and macrophages but not in liver. This differential regulation correlates with the presence of a critical LXR response element in the ME region of the ApoE gene.

Mice lacking ApoE expression develop atherosclerosis spontaneously on a normal chow diet and are a widely used model for the study of atherogenesis. Due to the importance of ApoE in lipoprotein clearance, mice lacking this protein exhibit greatly elevated plasma VLDL and intermediate-density lipoprotein cholesterol levels (37). However, several lines of evidence indicate that macrophage expression of ApoE also exerts an antiatherogenic effect. Mice expressing ApoE only in macrophages are protected against atherosclerosis, whereas those specifically lacking ApoE expression in macrophages are more susceptible (40, 41, 42). As ApoE is present in a gene cluster that contains ApoCI, ApoCII, and ApoCIV, and it was recently demonstrated that these Apo genes are also LXR responsive (43). Interestingly, all of these -helical secreted Apos have been shown to serve as acceptors in ABCA1-mediated cholesterol efflux. The elaboration of these acceptors by macrophages within the arterial wall would be expected to promote cholesterol efflux and reverse cholesterol transport. The ability of LXR to control expression of the entire ApoCI/ApoCII/ApoCIV cluster may explain why the ability of LXR agonists to inhibit atherosclerosis is not compromised in ApoE null mice (see below).

	LIPOPROTEIN REMODELING ENZYMES

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
LXR has also been shown to influence the expression of several enzymes that act on lipoproteins, including lipoprotein lipase (LPL), cholesterol ester transfer protein (CETP), and the phospholipid transfer protein (PLTP) (44, 45, 46, 47). LPL catalyzes the hydrolysis of lipoprotein triglycerides and is highly expressed in adipose tissue and muscle, and is also produced by macrophages (48). Similar to ApoE, the regulation of LPL gene expression by LXR is tissue specific. LXR agonists induce expression of LPL in liver and macrophages but not in adipose tissue (49). The contribution of LPL expression to atherogenesis is complex and likely to be context dependent. On the one hand, the hydrolysis of triglyceride-rich lipoprotein and the concomitant generation of material for HDL formation would be considered antiatherogenic. Indeed, systemic overproduction of human LPL in atherogenic animal models appears to protect against atherosclerosis and diet-induced atherogenesis (50, 51). On the other hand, evidence suggests that macrophage expression of LPL in the artery wall may be proatherogenic. LPL plays a role in binding of modified lipoproteins and may promote the conversion of triglyceride-rich lipoproteins to cholesterol-rich lipoproteins such as LDL. Macrophage-specific overproduction of LPL accelerates atherosclerosis in both ApoE-/- and LDLR-/- mice (52, 53). Thus, the tissue site of LPL expression appears to be a key determinant of its effects on atherosclerosis.

The LXR target genes CETP and PLTP and are both remodeling enzymes that transfer lipids between lipoproteins. CETP is secreted by the liver and circulates in plasma principally bound to HDL (54). CETP mediates the transfer of HDL cholesterol esters to ApoB-containing particles in exchange for triglycerides (55). The contribution of CETP activity to atherosclerosis susceptibility is not yet clear. One would predict that the transfer of cholesterol ester from mature HDL particles would generate pre-ß-HDL-like particles that would be antiatherogenic. However, overexpression of human CETP in atherosclerotic mice lowers plasma HDL levels and increases lesion formation (56). PLTP has been identified as a modulator of HDL metabolism and may also be involved in reverse cholesterol transport (57). During the lipolysis of serum VLDL by LPL, surface remnants containing phospholipids and Apos are transferred by PLTP and contribute to pre-ß-HDL. PLTP can also mediate lipid transfer between HDL particles to produce a small pre-ß-HDL and a large -HDL. Expression of a human PLTP transgene in mice increases production of pre-ß-HDL and enhances hepatic uptake and clearance of cholesterol ester (58, 59). In addition, PLTP has recently been shown to be critical for VLDL secretion from the liver. Surprisingly, PLTP-deficient mice exhibit markedly decreased levels of VLDL and LDL on and ApoE-deficient or ApoB-transgenic background (60). The ability of LXR agonists to raise plasma HDL, VLDL, and triglyceride levels may involve induction of PLTP expression in liver. However, LXR agonists also control PLTP expression in macrophages and this enzyme is expressed at high levels in atherosclerotic lesions (45). In the context of lesion macrophages, induction of PLTP expression by LXR is likely to be atheroprotective. Increased PLTP expression in the artery wall may serve to generate cholesterol acceptors and therefore contribute to cholesterol efflux. Tissue-specific knockout or bone marrow transplant experiments will be required to dissect the role of PLTP in these different contexts.

	LIPOGENESIS

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
Some of the earliest studies on LXR pointed to an important role for these receptors in the control of fatty acid as well as cholesterol metabolism. Mice carrying a targeted disruption in the LXR gene were noted to be deficient in the expression of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), steroyl coenzyme A desaturase 1 (SCD-1), and acyl coenzyme A carboxylase (ACC) (10). Consistent with these observations, administration of the synthetic LXR ligands to mice triggers induction of the lipogenic pathway and elevates plasma and hepatic triglyceride levels (14, 61). Although not immediately evident, the regulation of lipogenesis by LXR is consistent with the view of LXR as a cholesterol sensor. Free cholesterol is highly toxic to cells and esterification to fatty acids is an important mechanism for buffering free cholesterol levels. The primary mechanism by which LXR agonists stimulate lipogenesis appears to be through direct activation of the SREBP-1c promoter (62, 63). In addition to effects on SREBP-1c, direct actions of LXR on certain lipogenic genes such as FAS (61) and PLTP (44, 45) are also likely to contribute to the ability of LXR agonists to cause hypertriglyceridemia. Thus, although they have many beneficial effects on cholesterol metabolism as described above, LXR agonists have certain undesirable effects. At present, the lipogenic activity of LXR agonists represents a significant obstacle to the development of these compounds as drugs.

	LXRs AND ATHEROSCLEROSIS

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
Macrophage cholesteryl ester accumulation in the artery wall reflects a balance between scavenger receptor-mediated uptake and ABCA1-mediated cholesterol efflux. Thus, alterations in this balance that favor lipid removal via the efflux pathway would be predicted to limit foam cell formation and retard atherogenesis. Conversely, interference with the efflux pathway should exacerbate lesion development. Recent studies have directly addressed the role of the LXR signaling pathway in atherosclerosis using mouse models. As should be clear from the studies reviewed above, the diverse actions of LXRs in different tissues present a challenge to dissecting the roles of specific LXR-mediated effects in cardiovascular disease. Although tissue-specific knockouts of LXRs are not yet available, Tangirala and colleagues (27) were able to address the importance of macrophage LXR signaling using bone marrow transplantation studies into ApoE-/- and LDLR-/- mice. This approach allowed an analysis of LXR null macrophages in the setting of normal LXR function in liver and intestine. Transplantation of LXR null bone marrow led to a significant increase in atherosclerotic lesion formation in both ApoE null and LDLR null recipient mice. These studies provide strong evidence that LXR activity in macrophages is an important determinant of susceptibility to atherosclerosis.

Treatment of highly lipid-loaded macrophages in vitro with synthetic LXR ligands leads to a dose-dependent increase in LXR target gene expression, suggesting that a similar hyperactivation of the LXR pathway might be achieved within the vessel wall (64). Direct evidence for the potential utility of LXR activators in atherosclerosis has come from intervention studies in murine models. The LXR agonist GW3965 was shown to decrease lesion area approximately 50% in both ApoE null and LDLR null mice (64). A similar reduction in atherosclerosis was observed with the RXR agonist LG268 [which activates LXR/RXR as well as FXR/RXR and peroxisomal proliferator-activated protein (PPAR)/RXR] (65). Thus, despite the undesirable effects of LXR agonists on triglyceride levels, the net effect of whole body LXR activation is antiatherogenic. Chronic ligand administration only moderately affected the lipoprotein profile of these mice, suggesting that direct effect of ligand on cells of the artery wall may also be involved in the antiatherogenic effects. Consistent with this idea, ABCA1 and ABCG1 expression in the atherosclerotic aortas of ApoE null mice were significantly higher in mice treated with LXR agonist (64).

	LXRs AND INFLAMMATION

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
In an effort to further elucidate the molecular basis for the atheroprotective effects of LXRs, recent studies have explored other roles for these receptors in macrophage biology. In addition to their role in lipid metabolism outlined above, macrophages play a central role in innate immunity. They function to scavenge pathogens and apoptotic cells as well as to coordinate the inflammatory response to such stimuli through the production of cytokines, chemokines, and reactive oxygen species. Moreover, atherosclerosis is now recognized to be a chronic inflammatory disease as well as a disorder of lipid metabolism. Inflammatory mediators such as monocyte chemoattractant protein 1, IL-6, and IL-1ß promote monocyte recruitment and stimulate smooth muscle cell proliferation (66). Metalloproteinases such as matrix metalloproteinase-9 have been implicated in both lesion remodeling and plaque rupture (67, 68). Recently, LXR agonists were shown to antagonize the expression of a battery of inflammatory genes in activated macrophages (69). Consistent with these in vitro effects, LXR null mice exhibit enhanced responses to inflammatory stimuli and LXR ligands reduce inflammation in a murine model of contact dermatitis. In addition, treatment of ApoE mice with LXR agonists reduced the expression of the inflammatory mediator matrix metalloproteinase-9 in atherosclerotic aortas. Taken together, these observations suggest that LXR agonists may exert their antiatherogenic effects not only by promoting cholesterol efflux, but also by acting to limit the production of inflammatory mediators in the artery wall (Fig. 2). Additional studies will be required to determine the relative contributions of the lipid metabolic and inflammatory effects of LXR in atherosclerosis. The ability of LXRs to modulate inflammatory signaling in other disease contexts is also being explored.

View larger version (56K): [in this window] [in a new window]   Figure 2. The LXR Signaling Pathway in Macrophages Is Involved in Both the Promotion of Lipid Metabolism and Cholesterol Efflux and the Repression of Inflammatory Gene Expression

	CROSS-TALK WITH OTHER NUCLEAR RECEPTORS

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

	PERSPECTIVES

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 
It is now clear that LXRs play an important role in the maintenance of cellular and systemic lipid homeostasis in vertebrates. A number of important issues remain to be explored, however. For example, LXRs are also highly expressed in brain and adipose tissue. The role of LXR signaling in these contexts is not yet clear and is a subject of ongoing investigation. Given the close relationship between lipid and glucose metabolism, it is likely that LXRs may play a role in the coordination of glucose, fatty acid, and cholesterol metabolism. Finally, the role of LXRs in tissues such as skin, kidney, and the adrenals will also need to be addressed.

Pharmacological activation of LXRs in vivo by potent and efficacious synthetic ligands leads to a number of favorable changes in lipid metabolism, including promotion of reverse cholesterol transport, elevation of plasma HDL cholesterol, inhibition of cholesterol absorption, and the antagonism of inflammatory signaling. The relevance of these effects for the development of cardiovascular disease is clear from studies showing that synthetic LXR ligands inhibit atherosclerosis in animal models. At the same time, however, the potent lipogenic activity of the current generation of LXR agonists is a significant limitation. From a drug development standpoint, the most desirable LXR agonist would be one that was a strong inducer of ABCA1 and a strong suppressor of inflammatory gene expression yet lacked activity on the SREBP-1c and FAS promoters. Given the fact that LXR is the dominant receptor involved in control of hepatic lipogenesis, an LXRß-selective agonist might be particularly useful for the modulation of human lipid metabolism. Finally, the recent discovery of the antiinflammatory actions of LXRs raises the questions of whether these effects can be separated from effects on lipid metabolism and whether certain LXR agonists may have utility as antiinflammatory agents.

	ACKNOWLEDGMENTS

 
We are grateful to Damien Wilpitz for artwork.

	FOOTNOTES

 
P.T. is an Assistant Investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles, and D.J.M. is an Associate Investigator of the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center at Dallas.

Abbreviations: ABC, ATP binding cassette; Apo, apolipoprotein; CETP, cholesterol ester transfer protein; FAS, fatty acid synthase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LXR, liver X receptor; ME, multiple enhancer; PLTP, phospholipid transfer protein; PPAR, peroxisomal proliferator-activated protein; RXR, retinoid X receptor; SR-BI, scavenger receptor type BI; SREBP-1c, sterol regulatory element binding protein 1c; VLDL, very low-density lipoprotein.

Received for publication February 20, 2003. Accepted for publication April 1, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION LXRs: NUCLEAR RECEPTORS AS... ATP BINDING CASSETTE (ABC)... APOLIPOPROTEINS LIPOPROTEIN REMODELING ENZYMES LIPOGENESIS LXRs AND ATHEROSCLEROSIS LXRs AND INFLAMMATION CROSS-TALK WITH OTHER NUCLEAR... PERSPECTIVES REFERENCES

 

1. Glass CK, Witztum JL 2001 Atherosclerosis. The roadahead. Cell 104:503–516[CrossRef][Medline]
2. Lusis AJ 2000 Atherosclerosis. Nature 407:233–241[CrossRef][Medline]
3. Attie AD, Kastelein JP, Hayden MR 2001 Pivotal role of ABCA1in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J Lipid Res 42:1717–1726[Abstract/Free Full Text]
4. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD,Sparrow CP, Lund EG 2001 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276:38378–38387[Abstract/Free Full Text]
5. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ 1996An oxysterol signalling pathway mediated by the nuclear receptor LXR . Nature 383:728–731
6. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB,Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM 1997 Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140[Abstract/Free Full Text]
7. Repa JJ, Mangelsdorf DJ 2000 The role of orphan nuclearreceptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16:459–481[CrossRef][Medline]
8. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, MangelsdorfDJ 1995 LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:1033–1045[Abstract/Free Full Text]
9. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U,Rudling M, Angelin B, Bjorkhem I, Pettersson S, Gustafsson JA 2001 Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRß-deficient mice. J Clin Invest 107:565–573[Medline]
10. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, HammerRE, Mangelsdorf DJ 1998 Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR . Cell 93:693–704[CrossRef][Medline]
11. Dietschy JM, Turley SD 2002 Control of cholesterol turnover inthe mouse. J Biol Chem 277:3801–3804[Free Full Text]
12. Agellon LB, Drover VA, Cheema SK, Gbaguidi GF, Walsh A 2002Dietary cholesterol fails to stimulate the human cholesterol 7-hydroxylase gene (CYP7A1) in transgenic mice. J Biol Chem 277:20131–30134
13. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K,Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ 2000 Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289:1524–1529[Abstract/Free Full Text]
14. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, SchwendnerS, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B 2000 Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838[Abstract/Free Full Text]
15. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A,Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G 1999 The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351[CrossRef][Medline]
16. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van DamM, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J, Hayden MR 1999 Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–345[CrossRef][Medline]
17. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC,Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G 1999 Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355[CrossRef][Medline]
18. Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, CoskranT, Haghpassand M, Francone OL 2002 Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol 22:630–637[Abstract/Free Full Text]
19. Haghpassand M, Bourassa PA, Francone OL, Aiello RJ 2001Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest 108:1315–1320
20. van Eck M, Bos IS, Kaminski WE, Orso E, Rothe G, Twisk J,Bottcher A, Van Amersfoort ES, Christiansen-Weber TA, Fung-Leung WP, Van Berkel TJ, Schmitz G 2002 Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc Natl Acad Sci USA 99:6298–6303[Abstract/Free Full Text]
21. Joyce CW, Amar MJ, Lambert G, Vaisman BL, Paigen B,Najib-Fruchart J, Hoyt Jr RF, Neufeld ED, Remaley AT, Fredrickson DS, Brewer Jr HB, Santamarina-Fojo S 2002 The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci USA 99:407–412[Abstract/Free Full Text]
22. Singaraja RR, Fievet C, Castro G, James ER, Hennuyer N, CleeSM, Bissada N, Choy JC, Fruchart JC, McManus BM, Staels B, Hayden MR 2002 Increased ABCA1 activity protects against atherosclerosis. J Clin Invest 110:35–42[CrossRef][Medline]
23. Costet P, Luo Y, Wang N, Tall AR 2000 Sterol-dependenttransactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275:28240–28245[Abstract/Free Full Text]
24. Schwartz K, Lawn RM, Wade DP 2000 ABC1 gene expression andApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun 274:794–802[CrossRef][Medline]
25. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, WilpitzDC, Edwards PA, Tontonoz P 2000 Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR . Proc Natl Acad Sci USA 97:12097–12102[Abstract/Free Full Text]
26. Schuster GU, Parini P, Wang L, Alberti S, Steffensen KR,Hansson GK, Angelin B, Gustafsson JA 2002 Accumulation of foam cells in liver X receptor-deficient mice. Circulation 106:1147–1153[Abstract/Free Full Text]
27. Tangirala RK, Bischoff ED, Joseph SB, Wagner BL, Walczak R,Laffitte BA, Daige CL, Thomas D, Heyman RA, Mangelsdorf DJ, Wang X, Lusis AJ, Tontonoz P, Schulman IG 2002 Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc Natl Acad Sci USA 99:11896–11901[Abstract/Free Full Text]
28. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, MangelsdorfDJ, Edwards PA 2000 Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275:14700–14707[Abstract/Free Full Text]
29. Klucken J, Buchler C, Orso E, Kaminski WE, Porsch-Ozcurumez M,Liebisch G, Kapinsky M, Diederich W, Drobnik W, Dean M, Allikmets R, Schmitz G 2000 ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc Natl Acad Sci USA 97:817–822[Abstract/Free Full Text]
30. Lee MH, Lu K, Patel SB 2001 Genetic basis of sitosterolemia. Curr Opin Lipidol 12:141–149[CrossRef][Medline]
31. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J,Kwiterovich P, Shan B, Barnes R, Hobbs HH 2000 Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775[Abstract/Free Full Text]
32. Graf GA, Li WP, Gerard RD, Gelissen I, White A, Cohen JC,Hobbs HH 2002 Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest 110:659–669[CrossRef][Medline]
33. Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D,Cohen JC, Hobbs HH 2002 Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA 99:16237–16242[Abstract/Free Full Text]
34. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H,Mangelsdorf DJ 2002 Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors and ß. J Biol Chem 277:18793–18800[Abstract/Free Full Text]
35. Plosch T, Kok T, Bloks VW, Smit MJ, Havinga R, Chimini G,Groen AK, Kuipers F 2002 Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J Biol Chem 277:33870–33877[Abstract/Free Full Text]
36. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC,Hobbs HH 2002 Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 110:671–680[CrossRef][Medline]
37. Curtiss LK, Boisvert WA 2000 Apolipoprotein E andatherosclerosis. Curr Opin Lipidol 11:243–251[CrossRef][Medline]
38. Shih SJ, Allan C, Grehan S, Tse E, Moran C, Taylor JM 2000Duplicated downstream enhancers control expression of the human apolipoprotein E gene in macrophages and adipose tissue. J Biol Chem 275:31567–31572
39. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR,Mangelsdorf DJ, Tontonoz P 2001 LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98:507–512[Abstract/Free Full Text]
40. Bellosta S, Mahley RW, Sanan DA, Murata J, Newland DL, TaylorJM, Pitas RE 1995 Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. J Clin Invest 96:2170–2179
41. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, GleavesLA, Atkinson JB, Linton MF 1997 Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci USA 94:4647–4652[Abstract/Free Full Text]
42. Linton MF, Atkinson JB, Fazio S 1995 Prevention ofatherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 267:1034–1037[Abstract/Free Full Text]
43. Mak PA, Laffitte BA, Desrumaux C, Joseph SB, Curtiss LK,Mangelsdorf DJ, Tontonoz P, Edwards PA 2002 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 and ß. J Biol Chem 277:31900–21908[Abstract/Free Full Text]
44. Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR,Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC 2002 Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 277:39561–39565[Abstract/Free Full Text]
45. Laffitte BA, Joseph SB, Chen M, Castrillo A, Repa JJ, WilpitzDC, Mangelsdorf DJ, Tontonoz P 2003 The phospholipid transfer protein gene is an LXR target gene expressed by macrophages in atherosclerotic lesions. Mol Cell Biol 23:2182–2191[Abstract/Free Full Text]
46. Luo Y, Tall AR 2000 Sterol upregulation of human CETPexpression in vitro and in transgenic mice by an LXR element. J Clin Invest 105:513–520[Medline]
47. Mak PA, Kast-Woelbern HR, Anisfeld AM, Edwards PA 2002Identification 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 43:2037–2041
48. Goldberg IJ 1996 Lipoprotein lipase and lipolysis: centralroles in lipoprotein metabolism and atherogenesis. J Lipid Res 37:693–707[Abstract]
49. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ 2001 Regulationof lipoprotein lipase by the oxysterol receptors, LXR and LXRß. J Biol Chem 276:43018–43024[Abstract/Free Full Text]
50. Shimada M, Ishibashi S, Inaba T, Yagyu H, Harada K, Osuga JI,Ohashi K, Yazaki Y, Yamada N 1996 Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. Proc Natl Acad Sci USA 93:7242–7246[Abstract/Free Full Text]
51. Yagyu H, Ishibashi S, Chen Z, Osuga J, Okazaki M, Perrey S,Kitamine T, Shimada M, Ohashi K, Harada K, Shionoiri F, Yahagi N, Gotoda T, Yazaki Y, Yamada N 1999 Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice. J Lipid Res 40:1677–1685[Abstract/Free Full Text]
52. Babaev VR, Patel MB, Semenkovich CF, Fazio S, Linton MF 2000Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice. J Biol Chem 275:26293–26299
53. Wilson K, Fry GL, Chappell DA, Sigmund CD, Medh JD 2001Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein e knockout mice but not in C57BL/6 mice. Arterioscler Thromb Vasc Biol 21:1809–1815
54. Barter P 2000 CETP and atherosclerosis. Arterioscler ThrombVasc Biol 20:2029–2031[Free Full Text]
55. Oliveira HC, Ma L, Milne R, Marcovina SM, Inazu A, Mabuchi H,Tall AR 1997 Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation. Studies in CETP transgenic mice and human genetic CETP deficiency. Arterioscler Thromb Vasc Biol 17:1045–1052[Abstract/Free Full Text]
56. Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, BreslowJL, Tall AR 1999 Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol 19:1105–1110[Abstract/Free Full Text]
57. van Tol A 2002 Phospholipid transfer protein. Curr OpinLipidol 13:135–139[CrossRef][Medline]
58. Foger B, Santamarina-Fojo S, Shamburek RD, Parrot CL, TalleyGD, Brewer Jr HB 1997 Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL. J Biol Chem 272:27393–27400[Abstract/Free Full Text]
59. Jaari S, van Dijk KW, Olkkonen VM, van der Zee A, Metso J,Havekes L, Jauhiainen M, Ehnholm C 2001 Dynamic changes in mouse lipoproteins induced by transiently expressed human phospholipid transfer protein (PLTP): importance of PLTP in preß-HDL generation. Comp Biochem Physiol B Biochem Mol Biol 128:781–792[CrossRef][Medline]
60. Jiang XC, Bruce C, Mar J, Lin M, Ji Y, Francone OL, Tall AR1999 Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J Clin Invest 103:907–914
61. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE,Walczak R, Collins JL, Osborne TF, Tontonoz P 2002 Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277:11019–11025[Abstract/Free Full Text]
62. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, ShimomuraI, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ 2000 Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR and LXRß. Genes Dev 14:2819–2830[Abstract/Free Full Text]
63. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH,Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N 2001 Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 21:2991–3000[Abstract/Free Full Text]
64. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR,Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P 2002 Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA 99:7604–7609[Abstract/Free Full Text]
65. Claudel T, Leibowitz MD, Fievet C, Tailleux A, Wagner B, RepaJJ, Torpier G, Lobaccaro JM, Paterniti JR, Mangelsdorf DJ, Heyman RA, Auwerx J 2001 Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc Natl Acad Sci USA 98:2610–2615[Abstract/Free Full Text]
66. Hansson GK 1999 Inflammation and immune response inatherosclerosis. Curr Atheroscler Rep 1:150–155[Medline]
67. Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P 1995Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA 92:402–406
68. Pasterkamp G, Schoneveld AH, Hijnen DJ, de Kleijn DP, TeepenH, van der Wal AC, Borst C 2000 Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery. Atherosclerosis 150:245–253[CrossRef][Medline]
69. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ,Tontonoz P 2003 Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 13:213–219
70. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, GlassCK 2000 Peroxisome proliferator-activated receptor ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106:523–531[Medline]
71. Chawla A, Boisvert WA, Lee C, Laffitte BA, Barak Y, Joseph SB,Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P 2001 A PPAR-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171[CrossRef][Medline]
72. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, CollinsJL, Tontonoz P 2001 Autoregulation of the human liver X receptor promoter. Mol Cell Biol 21:7558–7568[Abstract/Free Full Text]
73. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, TorraIP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B 2001 PPAR- and PPAR- activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7:53–58[CrossRef][Medline]

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				D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]

				J. F. Oram and A. M. Vaughan ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease Circ. Res., November 10, 2006; 99(10): 1031 - 1043. [Abstract] [Full Text] [PDF]

				Y. Tateishi, R. Sonoo, Y.-i. Sekiya, N. Sunahara, M. Kawano, M. Wayama, R. Hirota, Y.-i. Kawabe, A. Murayama, S. Kato, et al. Turning Off Estrogen Receptor {beta}-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis Mol. Cell. Biol., November 1, 2006; 26(21): 7966 - 7976. [Abstract] [Full Text] [PDF]

				C. Marathe, M. N. Bradley, C. Hong, F. Lopez, C. M. R. de Galarreta, P. Tontonoz, and A. Castrillo The Arginase II Gene Is an Anti-inflammatory Target of Liver X Receptor in Macrophages J. Biol. Chem., October 27, 2006; 281(43): 32197 - 32206. [Abstract] [Full Text] [PDF]

				E. Ikonen Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev, October 1, 2006; 86(4): 1237 - 1261. [Abstract] [Full Text] [PDF]

				A. D. Watson Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Lipidomics: a global approach to lipid analysis in biological systems J. Lipid Res., October 1, 2006; 47(10): 2101 - 2111. [Abstract] [Full Text] [PDF]

				E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, G. U. Schuster, J.-A. Gustafsson, M. D. Basso, and P. Nambi Liver X Receptor (LXR)-beta Regulation in LXR{alpha}-Deficient Mice: Implications for Therapeutic Targeting Mol. Pharmacol., October 1, 2006; 70(4): 1340 - 1349. [Abstract] [Full Text] [PDF]

				L. R. Brunham, J. K. Kruit, T. D. Pape, J. S. Parks, F. Kuipers, and M. R. Hayden Tissue-Specific Induction of Intestinal ABCA1 Expression With a Liver X Receptor Agonist Raises Plasma HDL Cholesterol Levels Circ. Res., September 29, 2006; 99(7): 672 - 674. [Abstract] [Full Text] [PDF]

				K. Chu, M. Miyazaki, W. C. Man, and J. M. Ntambi 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., September 1, 2006; 26(18): 6786 - 6798. [Abstract] [Full Text] [PDF]

				H. Zitzer, W. Wente, M. B. Brenner, S. Sewing, K. Buschard, J. Gromada, and A. M. Efanov Sterol Regulatory Element-Binding Protein 1 Mediates Liver X Receptor-{beta}-Induced Increases in Insulin Secretion and Insulin Messenger Ribonucleic Acid Levels Endocrinology, August 1, 2006; 147(8): 3898 - 3905. [Abstract] [Full Text] [PDF]

				K. Aravindhan, C. L. Webb, M. Jaye, A. Ghosh, R. N. Willette, N. J. DiNardo, and B. M. Jucker Assessing the effects of LXR agonists on cellular cholesterol handling: a stable isotope tracer study J. Lipid Res., June 1, 2006; 47(6): 1250 - 1260. [Abstract] [Full Text] [PDF]

				T. R. Sweeney, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1313 - E1320. [Abstract] [Full Text] [PDF]

				M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF]

				J. Zhou, Y. Zhai, Y. Mu, H. Gong, H. Uppal, D. Toma, S. Ren, R. M. Evans, and W. Xie A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway J. Biol. Chem., May 26, 2006; 281(21): 15013 - 15020. [Abstract] [Full Text] [PDF]

				K. Abildayeva, P. J. Jansen, V. Hirsch-Reinshagen, V. W. Bloks, A. H. F. Bakker, F. C. S. Ramaekers, J. de Vente, A. K. Groen, C. L. Wellington,, F. Kuipers, et al. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux J. Biol. Chem., May 5, 2006; 281(18): 12799 - 12808. [Abstract] [Full Text] [PDF]

				R. J. Schmidt, J. V. Ficorilli, Y. Zhang, K. S. Bramlett, T. P. Beyer, K. Borchert, M. S. Dowless, K. A. Houck, T. P. Burris, P. I. Eacho, et al. A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity J. Lipid Res., May 1, 2006; 47(5): 1037 - 1044. [Abstract] [Full Text] [PDF]

				D. Walcher, A. Kummel, B. Kehrle, H. Bach, M. Grub, R. Durst, V. Hombach, and N. Marx LXR Activation Reduces Proinflammatory Cytokine Expression in Human CD4-Positive Lymphocytes Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1022 - 1028. [Abstract] [Full Text] [PDF]

				B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]

				L. Pei, A. Castrillo, and P. Tontonoz Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77 Mol. Endocrinol., April 1, 2006; 20(4): 786 - 794. [Abstract] [Full Text] [PDF]

				P. Costet, B. Cariou, G. Lambert, F. Lalanne, B. Lardeux, A.-L. Jarnoux, A. Grefhorst, B. Staels, and M. Krempf Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c J. Biol. Chem., March 10, 2006; 281(10): 6211 - 6218. [Abstract] [Full Text] [PDF]

				T. J. Kotti, D. M. O. Ramirez, B. E. Pfeiffer, K. M. Huber, and D. W. Russell Brain cholesterol turnover required for geranylgeraniol production and learning in mice PNAS, March 7, 2006; 103(10): 3869 - 3874. [Abstract] [Full Text] [PDF]

				G. D. Barish Peroxisome Proliferator-Activated Receptors and Liver X Receptors in Atherosclerosis and Immunity J. Nutr., March 1, 2006; 136(3): 690 - 694. [Abstract] [Full Text] [PDF]

				C.-H. Lee and J. Plutzky Liver X Receptor Activation and High-Density Lipoprotein Biology: A Reversal of Fortune? Circulation, January 3, 2006; 113(1): 5 - 8. [Full Text] [PDF]

				S. U. Naik, X. Wang, J. S. Da Silva, M. Jaye, C. H. Macphee, M. P. Reilly, J. T. Billheimer, G. H. Rothblat, and D. J. Rader Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo Circulation, January 3, 2006; 113(1): 90 - 97. [Abstract] [Full Text] [PDF]

				L. K. Curtiss, D. T. Valenta, N. J. Hime, and K.-A. Rye What Is So Special About Apolipoprotein AI in Reverse Cholesterol Transport? Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 12 - 19. [Abstract] [Full Text] [PDF]

				R. Koldamova, M. Staufenbiel, and I. Lefterov Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice J. Biol. Chem., December 30, 2005; 280(52): 43224 - 43235. [Abstract] [Full Text] [PDF]

				I. Weinhofer, M. Kunze, H. Rampler, A. L. Bookout, S. Forss-Petter, and J. Berger Liver X Receptor {alpha} Interferes with SREBP1c-mediated Abcd2 Expression: NOVEL CROSS-TALK IN GENE REGULATION J. Biol. Chem., December 16, 2005; 280(50): 41243 - 41251. [Abstract] [Full Text] [PDF]

				M. Chen, S. Beaven, and P. Tontonoz Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha J. Lipid Res., December 1, 2005; 46(12): 2570 - 2579. [Abstract] [Full Text] [PDF]

				E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice J. Lipid Res., December 1, 2005; 46(12): 2595 - 2604. [Abstract] [Full Text] [PDF]

				Y. Wang, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Downregulation of liver X receptor-{alpha} in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines J. Lipid Res., November 1, 2005; 46(11): 2377 - 2387. [Abstract] [Full Text] [PDF]

				J. F. Oram and J. W. Heinecke ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease Physiol Rev, October 1, 2005; 85(4): 1343 - 1372. [Abstract] [Full Text] [PDF]

				S. L. Sabol, H. B. Brewer Jr., and S. Santamarina-Fojo The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver J. Lipid Res., October 1, 2005; 46(10): 2151 - 2167. [Abstract] [Full Text] [PDF]

				E. Rigamonti, L. Helin, S. Lestavel, A.L. Mutka, M. Lepore, C. Fontaine, M.A. Bouhlel, S. Bultel, J.C. Fruchart, E. Ikonen, et al. Liver X Receptor Activation Controls Intracellular Cholesterol Trafficking and Esterification in Human Macrophages Circ. Res., September 30, 2005; 97(7): 682 - 689. [Abstract] [Full Text] [PDF]

				L. Pei, A. Castrillo, M. Chen, A. Hoffmann, and P. Tontonoz Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli J. Biol. Chem., August 12, 2005; 280(32): 29256 - 29262. [Abstract] [Full Text] [PDF]

				Z. Wang, T. Jiang, J. Li, G. Proctor, J. L. McManaman, S. Lucia, S. Chua, and M. Levi Regulation of Renal Lipid Metabolism, Lipid Accumulation, and Glomerulosclerosis in FVBdb/db Mice With Type 2 Diabetes Diabetes, August 1, 2005; 54(8): 2328 - 2335. [Abstract] [Full Text] [PDF]

				G. F. Lewis and D. J. Rader New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport Circ. Res., June 24, 2005; 96(12): 1221 - 1232. [Abstract] [Full Text] [PDF]

				I. Gerin, V. W. Dolinsky, J. G. Shackman, R. T. Kennedy, S.-H. Chiang, C. F. Burant, K. R. Steffensen, J.-A. Gustafsson, and O. A. MacDougald LXR{beta} Is Required for Adipocyte Growth, Glucose Homeostasis, and {beta} Cell Function J. Biol. Chem., June 17, 2005; 280(24): 23024 - 23031. [Abstract] [Full Text] [PDF]

				D. Ogawa, J. F. Stone, Y. Takata, F. Blaschke, V. H. Chu, D. A. Towler, R. E. Law, W. A. Hsueh, and D. Bruemmer Liver X Receptor Agonists Inhibit Cytokine-Induced Osteopontin Expression in Macrophages Through Interference With Activator Protein-1 Signaling Pathways Circ. Res., April 15, 2005; 96(7): e59 - e67. [Abstract] [Full Text] [PDF]

				B. C. Blaxall, J. M. Miano, and B. C. Berk Angiotensin II: A Devious Activator of Mineralocorticoid Receptor-Dependent Gene Expression Circ. Res., April 1, 2005; 96(6): 610 - 611. [Full Text] [PDF]

				Y. Watanabe, S. Jiang, W. Takabe, R. Ohashi, T. Tanaka, Y. Uchiyama, K. Katsumi, H. Iwanari, N. Noguchi, M. Naito, et al. Expression of the LXR{alpha} Protein in Human Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 622 - 627. [Abstract] [Full Text] [PDF]

				S. Lee, D.-K. Lee, E. Choi, and J. W. Lee Identification of a Functional Vitamin D Response Element in the Murine Insig-2 Promoter and Its Potential Role in the Differentiation of 3T3-L1 Preadipocytes Mol. Endocrinol., February 1, 2005; 19(2): 399 - 408. [Abstract] [Full Text] [PDF]

				B. D. Hegarty, A. Bobard, I. Hainault, P. Ferre, P. Bossard, and F. Foufelle From The Cover: Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory elementbinding protein-1c PNAS, January 18, 2005; 102(3): 791 - 796. [Abstract] [Full Text] [PDF]

				M. N. Bradley and P. Tontonoz Lesion Macrophages Are a Key Target for the Antiatherogenic Effects of LXR Agonists Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 10 - 11. [Full Text] [PDF]

				N. Levin, E. D. Bischoff, C. L. Daige, D. Thomas, C. T. Vu, R. A. Heyman, R. K. Tangirala, and I. G. Schulman Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 135 - 142. [Abstract] [Full Text] [PDF]

				F. Blaschke, O. Leppanen, Y. Takata, E. Caglayan, J. Liu, M. C. Fishbein, K. Kappert, K. I. Nakayama, A. R. Collins, E. Fleck, et al. Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries Circ. Res., December 10, 2004; 95(12): e110 - e123. [Abstract] [Full Text] [PDF]

				S. P. Anderson, C. Dunn, A. Laughter, L. Yoon, C. Swanson, T. M. Stulnig, K. R. Steffensen, R. A.S. Chandraratna, J.-A. Gustafsson, and J. C. Corton Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor {alpha}, Retinoid X Receptor, and Liver X Receptor in Mouse Liver Mol. Pharmacol., December 1, 2004; 66(6): 1440 - 1452. [Abstract] [Full Text] [PDF]

				H. Jakel, M. Nowak, E. Moitrot, H. Dehondt, D. W. Hum, L. A. Pennacchio, J. Fruchart-Najib, and J.-C. Fruchart The Liver X Receptor Ligand T0901317 Down-regulates APOA5 Gene Expression through Activation of SREBP-1c J. Biol. Chem., October 29, 2004; 279(44): 45462 - 45469. [Abstract] [Full Text] [PDF]

				J. C. Corton, U. Apte, S. P. Anderson, P. Limaye, L. Yoon, J. Latendresse, C. Dunn, J. I. Everitt, K. A. Voss, C. Swanson, et al. Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors J. Biol. Chem., October 29, 2004; 279(44): 46204 - 46212. [Abstract] [Full Text] [PDF]

				T. Kino and G. P. Chrousos Combating Atherosclerosis With LXR{alpha} And PPAR{alpha} Agonists: Is Rational Multitargeted Polypharmacy the Future of Therapeutics in Complex Diseases? Mol. Interv., October 1, 2004; 4(5): 254 - 257. [Abstract] [Full Text] [PDF]

				M. Agassandian, S. N. Mathur, J. Zhou, F. J. Field, and R. K. Mallampalli Oxysterols Trigger ABCA1-Mediated Basolateral Surfactant Efflux Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 227 - 233. [Abstract] [Full Text] [PDF]

				J. B. Seo, H. M. Moon, W. S. Kim, Y. S. Lee, H. W. Jeong, E. J. Yoo, J. Ham, H. Kang, M.-G. Park, K. R. Steffensen, et al. Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor {gamma} Expression Mol. Cell. Biol., April 15, 2004; 24(8): 3430 - 3444. [Abstract] [Full Text] [PDF]

				S. Hummasti, B. A. Laffitte, M. A. Watson, C. Galardi, L. C. Chao, L. Ramamurthy, J. T. Moore, and P. Tontonoz Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target J. Lipid Res., April 1, 2004; 45(4): 616 - 625. [Abstract] [Full Text] [PDF]

				R. Walczak, S. B. Joseph, B. A. Laffitte, A. Castrillo, L. Pei, and P. Tontonoz Transcription of the Vascular Endothelial Growth Factor Gene in Macrophages Is Regulated by Liver X Receptors J. Biol. Chem., March 12, 2004; 279(11): 9905 - 9911. [Abstract] [Full Text] [PDF]

				D. S. Ng, C. Xie, G. F. Maguire, X. Zhu, F. Ugwu, E. Lam, and P. W. Connelly Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance J. Biol. Chem., February 27, 2004; 279(9): 7636 - 7642. [Abstract] [Full Text] [PDF]

				M. Ricote, A. F. Valledor, and C. K. Glass Decoding Transcriptional Programs Regulated by PPARs and LXRs in the Macrophage: Effects on Lipid Homeostasis, Inflammation, and Atherosclerosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 230 - 239. [Abstract] [Full Text]

				W. A. Hsueh and D. Bruemmer Peroxisome Proliferator-Activated Receptor {gamma}: Implications for Cardiovascular Disease Hypertension, February 1, 2004; 43(2): 297 - 305. [Abstract] [Full Text] [PDF]

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