Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor Published, JLR Papers in Press, August 1, 2004. DOI 10.1194/jlr.M400257-JLR200

Liver X receptors (LXRs) play key roles in the regulation of cholesterol homeostasis by limiting cholesterol accumulation in macrophages within arterial wall lesion sites by a mechanism that includes the upregulation of ATP binding cassette transporters. These atheroprotective properties distinguish LXRs as potential targets for pharmaceutical intervention in cardiovascular disease. Their associated activity for promoting lipogenesis and triglyceride accretion through the activation of sterol-response element binding protein 1c (SREBP-1c) expression, however, represents a potential proatherogenic liability. A newly characterized synthetic oxysterol, N,N-dimethyl-3β-hydroxycholenamide (DMHCA), represents a gene-selective LXR modulator that mediates potent transcriptional activation of ABCA1 gene expression while exhibiting minimal effects on SREBP-1c both in vitro and in vivo in mice. DMHCA has the potential to stimulate cholesterol transport through the upregulation of LXR target genes, including ABCA1, in liver, small intestine, and peritoneal macrophages. Compared with known nonsteroidal LXR agonists, however, DMHCA exhibits only limited activity for increasing hepatic SREBP-1c mRNA and does not alter circulating plasma triglycerides. Cell-based studies also indicate that DMHCA enhances cholesterol efflux in macrophages and suggest a mechanism whereby this selective modulator can potentially inhibit cholesterol accumulation. DMHCA and related gene-selective ligands of LXR may have application to the study and treatment of atherosclerosis.

[1]  J. Gustafsson,et al.  Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice. , 2001, The Journal of clinical investigation.

[2]  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.

[3]  D. Mangelsdorf,et al.  Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. , 2000, Science.

[4]  L. Moore,et al.  Pharmacophore analysis of the nuclear oxysterol receptor LXRalpha. , 2001, Journal of medicinal chemistry.

[5]  T. Willson,et al.  Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages* , 2001, The Journal of Biological Chemistry.

[6]  D. Mangelsdorf,et al.  Role of LXRs in control of lipogenesis. , 2000, Genes & development.

[7]  J. Piette,et al.  Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1 , 1999, Nature Genetics.

[8]  S. Kliewer,et al.  Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. Sensen,et al.  Mutations in the ABC 1 gene in familial HDL deficiency with defective cholesterol efflux , 1999, The Lancet.

[10]  J. Gustafsson,et al.  OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Suzhen Li,et al.  Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism , 2002 .

[12]  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.

[13]  R. Lawn,et al.  ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. , 2000, Biochemical and biophysical research communications.

[14]  D. Mangelsdorf,et al.  LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Tall,et al.  Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. , 2000, The Journal of clinical investigation.

[16]  S. Liao,et al.  Hypolipidemic effects of selective liver X receptor alpha agonists , 2001, Steroids.

[17]  O. Francone,et al.  Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[18]  A. Tall,et al.  Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. , 2000, The Journal of biological chemistry.

[19]  R. Hammer,et al.  Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα , 1998, Cell.

[20]  M. Brown,et al.  Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. Fung-Leung,et al.  Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. McDonnell,et al.  Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators. , 2002, Recent progress in hormone research.

[23]  R. Hiipakka,et al.  Selective activation of liver X receptor alpha by 6α-hydroxy bile acids and analogs , 2000, Steroids.

[24]  H. Hobbs,et al.  Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors α and β* , 2002, The Journal of Biological Chemistry.

[25]  R. Hiipakka,et al.  Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Langmann,et al.  The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease , 1999, Nature Genetics.

[27]  D. Mangelsdorf,et al.  Human White/Murine ABC8 mRNA Levels Are Highly Induced in Lipid-loaded Macrophages , 2000, The Journal of Biological Chemistry.

[28]  R. Walczak,et al.  Autoregulation of the Human Liver X Receptor α Promoter , 2001, Molecular and Cellular Biology.

[29]  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.

[30]  A. Zwinderman,et al.  Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study , 2002, The Lancet.

[31]  N. Grishin,et al.  Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. , 2000, Science.

[32]  C. Sensen,et al.  Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency , 1999, Nature Genetics.

[33]  Mary K. Bennett,et al.  Sterol Regulation of Fatty Acid Synthase Promoter , 1995, The Journal of Biological Chemistry.

[34]  Jean-Marc A. Lobaccaro,et al.  Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ , 2000 .

[35]  Hitoshi Shimano,et al.  Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter , 2001, Molecular and Cellular Biology.

[36]  Peter Tontonoz,et al.  Direct and Indirect Mechanisms for Regulation of Fatty Acid Synthase Gene Expression by Liver X Receptors* , 2002, The Journal of Biological Chemistry.

[37]  Shutsung Liao,et al.  Cholestenoic Acid Is a Naturally Occurring Ligand for Liver X Receptor α* * This work was supported by NIH grants. , 2000, Endocrinology.

[38]  D. Mangelsdorf,et al.  An oxysterol signalling pathway mediated by the nuclear receptor LXRα , 1996, Nature.

[39]  Timothy M Willson,et al.  Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. , 2002, Journal of medicinal chemistry.

[40]  Timothy M. Willson,et al.  Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway* , 1997, The Journal of Biological Chemistry.

[41]  K. Umesono,et al.  LXR, a nuclear receptor that defines a distinct retinoid response pathway. , 1995, Genes & development.

[42]  B. Spiegelman,et al.  ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. , 1996, Genes & development.

[43]  R. Hammer,et al.  Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. , 1996, The Journal of clinical investigation.