Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target

Abstract

Ligand activation of liver X receptors (LXRs) has been shown to impact both lipid metabolism and inflammation. One complicating factor in studies utilizing synthetic LXR agonists is the potential for pharmacologic and receptor-independent effects. Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter. These mice exhibit increased LXR signaling selectively in adipose and macrophages. Analysis of gene expression in primary macrophages derived from two independent VP16-LXRα transgenic lines confirmed the ability of LXR to drive expression of genes involved in cholesterol efflux and fatty acid synthesis. Moreover, VP16-LXRα expression also suppressed the induction of inflammatory genes by lipopolysaccharide to a comparable degree as synthetic agonist. We further utilized VP16-LXRα-expressing macrophages to identify and validate new targets for LXRs, including the gene encoding ADP-ribosylation factor-like 7 (ARL7). ARL7 has previously been shown to transport cholesterol to the membrane for ABCA1-associated removal and thus may be integral to the LXR-dependent efflux pathway. We show that the ARL7 promoter contains a functional LXRE and can be transactivated by LXRs in a sequence-specific manner, indicating that ARL7 is a direct target of LXR. These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages. Ligand activation of liver X receptors (LXRs) has been shown to impact both lipid metabolism and inflammation. One complicating factor in studies utilizing synthetic LXR agonists is the potential for pharmacologic and receptor-independent effects. Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter. These mice exhibit increased LXR signaling selectively in adipose and macrophages. Analysis of gene expression in primary macrophages derived from two independent VP16-LXRα transgenic lines confirmed the ability of LXR to drive expression of genes involved in cholesterol efflux and fatty acid synthesis. Moreover, VP16-LXRα expression also suppressed the induction of inflammatory genes by lipopolysaccharide to a comparable degree as synthetic agonist. We further utilized VP16-LXRα-expressing macrophages to identify and validate new targets for LXRs, including the gene encoding ADP-ribosylation factor-like 7 (ARL7). ARL7 has previously been shown to transport cholesterol to the membrane for ABCA1-associated removal and thus may be integral to the LXR-dependent efflux pathway. We show that the ARL7 promoter contains a functional LXRE and can be transactivated by LXRs in a sequence-specific manner, indicating that ARL7 is a direct target of LXR. These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages. Coronary heart disease remains one of the leading causes of death in the industrialized world. Early atherosclerotic plaques are composed largely of macrophages that have been converted to foam cells following uptake of modified lipoproteins and other cellular debris (1Gill S. Chow R. Brown A.J. Sterol regulators of cholesterol homeostasis and beyond: The oxysterol hypothesis revisited and revised.Prog. Lipid Res. 2008; 47: 391-404Crossref PubMed Scopus (179) Google Scholar). The inability of macrophages to efflux sufficient amounts of engorged cholesterol to the reverse cholesterol transport (RCT) pathway contributes significantly to foam cell formation (1Gill S. Chow R. Brown A.J. Sterol regulators of cholesterol homeostasis and beyond: The oxysterol hypothesis revisited and revised.Prog. Lipid Res. 2008; 47: 391-404Crossref PubMed Scopus (179) Google Scholar, 2Tiwari R.L. Singh V. Barthwal M.K. Macrophages: an elusive yet emerging therapeutic target of atherosclerosis.Med. Res. Rev. 2007; 4: 483-544Google Scholar). Understanding the molecular mechanisms governing lesion development and macrophage cholesterol efflux will be essential to unraveling the pathogenesis of atherosclerosis. Previous studies have established that the RCT pathway is regulated by members of the nuclear receptor superfamily, specifically liver X receptor/retinoid X receptor (LXR/RXR) heterodimers (3Peet D.J. Janowski B.A. Mangelsdorf D.J. The LXRs: a new class of oxysterol receptors.Curr. Opin. Genet. Dev. 1998; 8: 571-575Crossref PubMed Scopus (324) Google Scholar, 4Peet 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 LXR alpha.Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1252) Google Scholar, 5Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.Nature. 1996; 383: 728-731Crossref PubMed Scopus (1477) Google Scholar, 6Willy 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: 1033-1045Crossref PubMed Scopus (923) Google Scholar). 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Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands.J. Biol. Chem. 2006; 281: 27816-27826Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). The two LXR isotypes (a and b) share a high degree of sequence homology in spite of a diverging expression pattern. LXRβ is found ubiquitously, whereas LXRα is expressed primarily in the liver, intestine, adipose, and macrophages (9Mangelsdorf D.J. Evans R.M. The RXR heterodimers and orphan receptors.Cell. 1995; 83: 841-850Abstract Full Text PDF PubMed Scopus (2843) Google Scholar). Analysis of mice lacking one or both LXR isotypes have revealed a key role for LXR signaling in bile acid synthesis, cellular cholesterol efflux and the movement of cholesterol through high density lipoproteins to the liver for excretion via the RCT pathway (4Peet 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 LXR alpha.Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1252) Google Scholar, 10Joseph S.B. Castrillo A. Laffitte B.A. Mangelsdorf D.J. Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.Nat. Med. 2003; 9: 213-219Crossref PubMed Scopus (1015) Google Scholar, 11Zelcer N. Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling.J. Clin. Invest. 2006; 116: 607-614Crossref PubMed Scopus (775) Google Scholar, 12Hong C. Tontonoz P. Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors.Curr. Opin. Genet. Dev. 2008; 18: 461-467Crossref PubMed Scopus (182) Google Scholar). In macrophages, LXRs directly regulate the expression of a battery of genes involved in cholesterol transport, including ABCA1, ABCG1, apolipoprotein (apo)E, LPL, and phospholipid transfer protein (13Repa 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, LXRalpha and LXRbeta.Genes Dev. 2000; 14: 2819-2830Crossref PubMed Scopus (1423) Google Scholar, 14Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc. Natl. Acad. Sci. USA. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 15Repa J.J. Mangelsdorf D.J. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.Annu. Rev. Cell Dev. Biol. 2000; 16: 459-481Crossref PubMed Scopus (609) Google Scholar, 16Zhang Y. Repa J.J. Gauthier K. Mangelsdorf D.J. Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta.J. Biol. Chem. 2001; 276: 43018-43024Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). LXRs also regulate the absorption of cholesterol from the intestine and its excretion from the liver through regulation of ABCG5 and ABCG8 expression (14Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion.Proc. Natl. Acad. Sci. USA. 2002; 99: 16237-16242Crossref PubMed Scopus (610) Google Scholar, 17Venkateswaran A. Laffitte B.A. Joseph S.B. Mak P.A. Wilpitz D.C. Edwards P.A. Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha.Proc. Natl. Acad. Sci. USA. 2000; 97: 12097-12102Crossref PubMed Scopus (848) Google Scholar, 18Laffitte 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: 507-512Crossref PubMed Scopus (576) Google Scholar, 19Repa 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 alpha and beta.J. Biol. Chem. 2002; 277: 18793-18800Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar). Targeted activation of LXR by synthetic agonists promotes cholesterol efflux from macrophages and protects against the development of atherosclerosis in mice (11Zelcer N. Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling.J. Clin. Invest. 2006; 116: 607-614Crossref PubMed Scopus (775) Google Scholar, 20Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Synthetic LXR ligand inhibits the development of atherosclerosis in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 7604-7609Crossref PubMed Scopus (787) Google Scholar). In addition to their functions in cholesterol homeostasis, LXRs have also emerged as regulators of inflammatory gene expression and innate immunity (11Zelcer N. Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling.J. Clin. Invest. 2006; 116: 607-614Crossref PubMed Scopus (775) Google Scholar, 21Bradley M.N. Hong C. Chen M. Joseph S.B. Wilpitz D.C. Wang X. Lusis A.J. Collins A. Hseuh W.A. Collins J.L. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.J. Clin. Invest. 2007; 117: 2337-2346Crossref PubMed Scopus (225) Google Scholar). Ligand-activated LXR inhibits the induction of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and monocyte chemotactic protein-1 (MCP-1) in response to inflammatory stimuli (22Castrillo A. Joseph S.B. Marathe C. Mangelsdorf D.J. Tontonoz P. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages.J. Biol. Chem. 2003; 278: 10443-10449Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 23Castrillo A. Joseph S.B. Vaidya S.A. Haberland M. Fogelman A.M. Cheng G. Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.Mol. Cell. 2003; 12: 805-816Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 24Joseph S.B. Bradley M.N. Castrillo A. Bruhn K.W. Mak P.A. Pei L. Hogenesch J. O'Connell R.M. Cheng G. Saez E. Miller J.F. Tontonoz P. LXR-dependent gene expression is important for macrophage survival and the innate immune response.Cell. 2004; 119: 299-309Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar). Additional studies have demonstrated that activation of TLR3 and TLR4 by bacterial and viral components inhibits LXR signaling, suggesting that LXR functions to regulate cross-talk between inflammatory and metabolic pathways. Finally, LXR ligands ameliorate inflammation in several in vivo assays, including murine models of contact dermatitis and atherosclerosis (10Joseph S.B. Castrillo A. Laffitte B.A. Mangelsdorf D.J. Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.Nat. Med. 2003; 9: 213-219Crossref PubMed Scopus (1015) Google Scholar, 20Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Synthetic LXR ligand inhibits the development of atherosclerosis in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 7604-7609Crossref PubMed Scopus (787) Google Scholar, 21Bradley M.N. Hong C. Chen M. Joseph S.B. Wilpitz D.C. Wang X. Lusis A.J. Collins A. Hseuh W.A. Collins J.L. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.J. Clin. Invest. 2007; 117: 2337-2346Crossref PubMed Scopus (225) Google Scholar, 23Castrillo A. Joseph S.B. Vaidya S.A. Haberland M. Fogelman A.M. Cheng G. Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.Mol. Cell. 2003; 12: 805-816Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter (25Graves R.A. Tontonoz P. Platt K.A. Ross S.R. Spiegelman B.M. Identification of a fat cell enhancer: analysis of requirements for adipose tissue-specific gene expression.J. Cell. Biochem. 1992; 49: 219-224Crossref PubMed Scopus (61) Google Scholar, 26Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar). These mice exhibit increased LXR signaling selectively in adipose tissue and macrophages, and confirm the ability of LXR to regulate pathways for lipid metabolism and inflammation independently of exogenous ligands. To further increase our understanding of the role of LXR in metabolism and inflammation, we employed this transgenic model to identify new LXR target genes. ADP riboyslation factor-like 7 (ARL7) was identified as a novel target gene. Members of the ARL family have between 40% and 60% sequence homology. Members of the ADP riboyslation factor (ARF) GTP-binding protein family have been shown to be involved in intracellular trafficking S.R. not Cell Biol. 2004; 14: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. F. S. Y. A. ADP-ribosylation factor and 7 a of the family by and a nuclear PubMed Scopus Google Scholar, R.A. J. M. S. A. for the family of GTP-binding and Cell Biol. 2006; PubMed Scopus Google Scholar, R.A. L. B. P. Y. C. L. family in membrane and PubMed Scopus Google Scholar, S. L. J. and a family of GTP-binding a for 2002; PubMed Scopus Google Scholar). a of this has been in macrophage cholesterol efflux S. C. F. S. Y. A. ADP-ribosylation factor and 7 a of the family by and a nuclear PubMed Scopus Google Scholar, A. G. S. B. S. P. M. G. ADP-ribosylation factor 7 (ARL7) is by cholesterol and in apolipoprotein cholesterol 2004; PubMed Scopus Google Scholar). We identified ARL7 as a direct LXR target gene both and the that ARL7 is involved in the LXR-dependent cholesterol efflux pathway. The LXR agonists and by and Collins RXR was by Heyman in in cell LXR ligands whereas RXR ligand was was from and B.A. A.M. Brown A.M. of in the Res. 2008; PubMed Scopus Google from from expressing murine LXRα the and by cells to cell for an aP2 was to a constitutively active receptor (25Graves R.A. Tontonoz P. Platt K.A. Ross S.R. Spiegelman B.M. Identification of a fat cell enhancer: analysis of requirements for adipose tissue-specific gene expression.J. Cell. Biochem. 1992; 49: 219-224Crossref PubMed Scopus (61) Google Scholar, 26Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (2005) Google Scholar). mice generated by of the a the of lines identified and was from One of was reverse the an sequence show of to The are in a a and and mice on a by of The transgenic mice on generated by our independent for on of expression and activation of LXR target genes. in and ligand mice or of a for the by the and of the of cell lines and cells in macrophages from mice gene expression cells in acid or ligand for LXR as for was and by macrophage inflammatory cells in acid or ligand for LXR for or or for was and by cells in and for and ligand for LXR by analysis from cell from for for from and from To further our understanding of the of LXR we a gain-of-function mouse transgenic expression was to an activation protein the control of the aP2 promoter The expression of aP2 is to adipose tissue and macrophages, as is to Moreover, the addition of the activation was to a constitutively active analysis confirmed expression as as increased LXRα expression in primary macrophages derived from two independent lines In analysis that the was expressed selectively in adipose tissue and macrophages and not We and have previously shown that LXRs to the regulation of genes involved in lipid metabolism in adipose transgenic mice generated to the potential of adipose tissue LXR signaling to lipid studies synthetic LXR transgenic mice increased expression of the LXR target genes and protein in both and adipose that the protein functions as a constitutively active receptor in vivo to our we have not in lipid or metabolism in the transgenic lines not have established that in macrophages, LXR an integral role in both lipid metabolism and inflammatory pathways. LXRs regulate the of genes directly involved in the cholesterol efflux pathway. The macrophages derived from two lines of transgenic mice an increased expression of LXR target including ABCA1, and and not not LXR target genes in transgenic macrophages. expression of and was not demonstrated the protein the ability to be by ligand the induction of LXR target genes and not Finally, analysis confirmed expression of protein in transgenic macrophages we the impact of the on inflammatory gene expression in macrophages. Previous studies have employed synthetic LXR agonists as to show that ligand activation of LXR the induction of inflammatory genes such as and factor in response to and other inflammatory stimuli (10Joseph S.B. Castrillo A. Laffitte B.A. Mangelsdorf D.J. Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.Nat. Med. 2003; 9: 213-219Crossref PubMed Scopus (1015) Google Scholar, 23Castrillo A. Joseph S.B. Vaidya S.A. Haberland M. Fogelman A.M. Cheng G. Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.Mol. Cell. 2003; 12: 805-816Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar). One of this is the potential for pharmacologic and receptor-independent effects. We constitutively active LXR also inflammatory gene shown in induction of and gene expression in response to was significantly in macrophages derived from both transgenic in the gene activation the also the of exogenous LXR agonists repression of inflammatory target genes was also for and We also confirmed that of protein in transgenic macrophages of and transgenic macrophages for an of LXR expression on macrophage activation of macrophages is to macrophage Activation is including increased and Activation of the LXR pathway in macrophages transgenic macrophages to in the of exogenous LXR the from our LXR transgenic model of the ability of LXR to regulate gene expression to lipid metabolism and inflammation in macrophages. We further primary macrophages from transgenic mice in cells LXRα to for previously LXR genes. our studies target genes such as ABCA1, ABCG1, and In studies also to the of ARL7 as a gene to LXR expression and synthetic LXR ligand analysis that ARL7 expression was expressed in macrophages derived from transgenic mice ARL7 expression was by the LXR and the RXR in cells of was as a response to ligands was in the macrophage cell indicating that ARL7 regulation by LXR is To the studies synthetic we also ARL7 regulation in macrophages lacking LXR macrophages and macrophages from and shown in expression of ARL7 was in response to LXR in and macrophages, indicating that LXR is of of both LXRs in the of ARL7 LXR target genes such as regulation of ARL7 expression was in To further studies to the ability of LXR ligands to ARL7 expression in mice or for and various for gene expression ARL7 increased significantly in the and of ligand in vivo regulation by LXRs To ARL7 was a direct target for LXR cells expressing LXR ligand in the or of an of protein synthesis. shown in induction of ARL7 expression by LXR was in the of indicating that new protein is not for the of LXR on analysis of the ARL7 identified two LXR response a and to the to the ability of heterodimers to the ARL7 shown in in LXRα and protein to a the ARL7 LXRE a of this sequence was to of an LXR a the of LXR in the In an of not ARL7 LXRE was to for formation Finally, we the ability of LXR to the ARL7 promoter in The sequence from to to the and the sequence from to the of LXR and RXR expression of the promoter not the lacking the LXRE addition of LXR a further increase in in an identify ARL7 as a direct target of LXR in macrophages. The nuclear receptors LXRα and have been shown to important in both inflammatory and metabolic pathways. studies have on synthetic LXR ligands and in have our understanding of LXR inflammatory the potential for of the ligand remains a in Here, we describe a novel in vivo model in LXRα is constitutively expressed in macrophages and adipose tissue yet remains to synthetic and ligands. In two lines of transgenic the constitutively active LXR regulated target genes in the of in this the macrophages against inflammatory stimuli such as as demonstrated by the repression of inflammatory genes such as and Ligand activation of LXR an increase in repression of the inflammatory genes. Moreover, transgenic macrophages to These studies provide in vivo for the and the of LXR. The ADP riboyslation factor (ARF) GTP-binding protein family of and the and ARL7 and a that are to one by a nuclear S. C. F. S. Y. A. ADP-ribosylation factor and 7 a of the family by and a nuclear PubMed Scopus Google Scholar). by A. G. S. B. S. P. M. G. ADP-ribosylation factor 7 (ARL7) is by cholesterol and in apolipoprotein cholesterol 2004; PubMed Scopus Google demonstrated that ARL7 is involved in the movement of cholesterol from the to for through the RCT pathway. studies have shown that members of this family S. L. J. and a family of GTP-binding a for 2002; PubMed Scopus Google Scholar, Y. ADP-ribosylation factor 7 (ARL7) and intracellular Res. PubMed Scopus Google and has to a role for ARL7 in intracellular transport Y. ADP-ribosylation factor 7 (ARL7) and intracellular Res. PubMed Scopus Google Scholar, I. J.G. M. K. Wang Goodman M. An promotes the transport of by Full Text Full Text PDF PubMed Scopus Google Scholar). molecular assays, we demonstrated that ARL7 is a LXR target gene. ARL7 was identified as through analysis of cells and the transgenic macrophages M.N. Hong C. Chen M. Joseph S.B. Wilpitz D.C. Wang X. Lusis A.J. Collins A. Hseuh W.A. Collins J.L. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE.J. Clin. Invest. 2007; 117: 2337-2346Crossref PubMed Scopus (225) Google Scholar, C. Bradley M.N. Hong C. F. Tontonoz P. Castrillo A. The gene is an target of liver X receptor in macrophages.J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar). studies of macrophages from and LXR mice LXR ligand revealed that both receptors independently regulate ARL7 and induction was in the of both a LXR response was identified in the ARL7 promoter that the and regulated from the promoter. studies have the activation of pathways in lipid metabolism by LXR as as repression of inflammatory pathways. These ARL7 is a LXR target gene the molecular by ARL7 cholesterol metabolism remains studies or may the of ARL7 activation and functions its family The of LXR as a regulator of cholesterol metabolism that ARL7 be a to regulatory pathways in lipid ADP riboyslation factor ADP-ribosylation factor-like liver X receptor reverse cholesterol transport retinoid X receptor protein