Liver X Receptor Signaling Pathways and Atherosclerosis

First discovered as orphan receptors, liver X receptors (LXRs) were subsequently identified as the nuclear receptor target of the cholesterol metabolites, oxysterols. There are 2 LXR receptors encoded by distinct genes: LXR&agr; is most highly expressed in the liver, adipose, kidney, adrenal tissues, and macrophages and LXR&bgr; is ubiquitously expressed. Despite differential tissue distribution, these isoforms have 78% homology in their ligand-binding domain and appear to respond to the same endogenous ligands. Work over the past 10 years has shown that the LXR pathway regulates lipid metabolism and inflammation via both the induction and repression of target genes. Given the importance of cholesterol regulation and inflammation in the development of cardiovascular disease, it is not surprising that activation of the LXR pathway attenuates various mechanisms underlying atherosclerotic plaque development. In this brief review, we will discuss the impact of the LXR pathway on both cholesterol metabolism and atherosclerosis.

[1]  Chao-ke Tang,et al.  The Effect of T0901317 on ATP-binding Cassette Transporter A1 and Niemann-Pick Type C1 in ApoE−/− Mice , 2008, Journal of cardiovascular pharmacology.

[2]  A. Lusis,et al.  Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE , 2007 .

[3]  G. Cheng,et al.  Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. , 2003, Molecular cell.

[4]  A. E. Sippel,et al.  Effect of Macrophage Overexpression of Murine Liver X Receptor-α (LXR-α) on Atherosclerosis in LDL-Receptor Deficient Mice , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[5]  Chao-ke Tang,et al.  Liver X receptor agonist T0901317 reduces atherosclerotic lesions in apoE-/- mice by up-regulating NPC1 expression , 2008, Science in China Series C: Life Sciences.

[6]  Y. Morikawa,et al.  T‐0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor‐deficient mice , 2003, FEBS letters.

[7]  M. Miyazaki,et al.  Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia , 2009, Journal of Lipid Research.

[8]  Peter Tontonoz,et al.  Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. , 2009, Immunity.

[9]  P. Nambi,et al.  LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse[S] , 2009, Journal of Lipid Research.

[10]  G. Norata,et al.  Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells. , 2005, International journal of molecular medicine.

[11]  P. Edwards,et al.  Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Fumiaki Sato,et al.  7-ketocholesterol, a major oxysterol, promotes pi-induced vascular calcification in cultured smooth muscle cells. , 2008, Journal of atherosclerosis and thrombosis.

[13]  G. Getz,et al.  Differential anti-atherosclerotic effects in the innominate artery and aortic sinus by the liver X receptor agonist T0901317. , 2009, Atherosclerosis.

[14]  S. Bornstein,et al.  Toll-like receptors, endocrine stress response, and arteriosclerosis. , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[15]  P. Tontonoz,et al.  LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor , 2009, Science.

[16]  T. Simon,et al.  Defective Mer Receptor Tyrosine Kinase Signaling in Bone Marrow Cells Promotes Apoptotic Cell Accumulation and Accelerates Atherosclerosis , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[17]  Xian Wang,et al.  Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR). , 2005, Cardiovascular research.

[18]  Christopher K. Glass,et al.  Atherosclerosis The Road Ahead , 2001, Cell.

[19]  F. Bussolino,et al.  LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms. , 2009, Atherosclerosis.

[20]  Aldons J. Lusis,et al.  Identification of macrophage liver X receptors as inhibitors of atherosclerosis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Sunagawa,et al.  Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1 , 2008, Hypertension.

[22]  K. Watson,et al.  TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. , 1994, The Journal of clinical investigation.

[23]  Andrew C. Li,et al.  Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. , 2010, Journal of lipid research.

[24]  G. Getz,et al.  Antiatherosclerotic Effects of a Novel Synthetic Tissue-Selective Steroidal Liver X Receptor Agonist in Low-Density Lipoprotein Receptor-Deficient Mice , 2008, Journal of Pharmacology and Experimental Therapeutics.

[25]  C. Daige,et al.  Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[26]  I. Tabas,et al.  Macrophage Apoptosis in Advanced Atherosclerosis , 2009, Annals of the New York Academy of Sciences.

[27]  P. Shah,et al.  TLR/MyD88 and Liver X Receptor α Signaling Pathways Reciprocally Control Chlamydia pneumoniae-Induced Acceleration of Atherosclerosis1 , 2008, The Journal of Immunology.

[28]  E. Schleicher,et al.  Induction of stearoyl-CoA desaturase protects human arterial endothelial cells against lipotoxicity. , 2008, American journal of physiology. Endocrinology and metabolism.

[29]  S. Chien,et al.  Laminar shear stress up-regulates the expression of stearoyl-CoA desaturase-1 in vascular endothelial cells. , 2007, Cardiovascular research.

[30]  M. Cooper,et al.  The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation , 2008, Diabetologia.

[31]  C. Glass,et al.  Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. , 2009, Genes & development.

[32]  J. Gustafsson,et al.  Accumulation of Foam Cells in Liver X Receptor-Deficient Mice , 2002, Circulation.

[33]  Peter Tontonoz,et al.  Liver X Receptor-dependent Repression of Matrix Metalloproteinase-9 Expression in Macrophages* , 2003, The Journal of Biological Chemistry.

[34]  P. Nambi,et al.  GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II‐mediated pressor responses in Sprague–Dawley rats , 2007, British journal of pharmacology.

[35]  Ji Young Kim,et al.  Up-regulation of skeletal muscle LIM protein 1 gene by 25-hydroxycholesterol may mediate morphological changes of rat aortic smooth muscle cells. , 2007, Life sciences.

[36]  A. Tall,et al.  Stearoyl-CoA Desaturase Inhibits ATP-binding Cassette Transporter A1-mediated Cholesterol Efflux and Modulates Membrane Domain Structure* , 2003, The Journal of Biological Chemistry.

[37]  E. Fleck,et al.  Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries , 2004, Circulation research.

[38]  Y. Tintut,et al.  T0901317, an LXR agonist, augments PKA‐induced vascular cell calcification , 2009, FEBS letters.

[39]  Yi Fu,et al.  Laminar Shear Stress Regulates Liver X Receptor in Vascular Endothelial Cells , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[40]  Peter Tontonoz,et al.  The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2* , 2010, The Journal of Biological Chemistry.

[41]  T. Langmann,et al.  Native LDL Upregulation of ATP‐Binding Cassette Transporter‐1 in Human Vascular Endothelial Cells , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[42]  T. Willson,et al.  Synthetic LXR ligand inhibits the development of atherosclerosis in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.