Convergence of lipid homeostasis through liver X and thyroid hormone receptors

Members of the nuclear receptor gene family act as biological rheostats to maintain metabolic homeostasis in response to endocrine and nutritional changes. The liver X (LXR) and thyroid hormone (TR) receptors have been shown to regulate overlapping but distinct metabolic pathways important for overall lipid homeostasis. Dyslipidemia is one out of four key determinants for cardiovascular risk and both LXRs and TRs may provide attractive targets for intervention of cardiovascular disease. In this review we will compare the two receptor systems to highlight similarities and differences in structure and function with implications for development of novel treatments for dyslipidemia and atherosclerosis.

[1]  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.

[2]  J. Gustafsson,et al.  Putative metabolic effects of the liver X receptor (LXR). , 2004, Diabetes.

[3]  F. Claessens,et al.  Structural basis of androgen receptor binding to selective androgen response elements. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  N. Powe,et al.  Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. , 2000, The Journal of clinical endocrinology and metabolism.

[5]  H. Nar,et al.  Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist. , 2004, Journal of molecular biology.

[6]  R. Mason,et al.  Blood Cholesterol Values in Hyperthyroidism and Hypothyroidism — Their Significance , 1930 .

[7]  Johan Malm,et al.  Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta. , 2004, Bioorganic & medicinal chemistry letters.

[8]  D. Nelson,et al.  Cytochrome P450 and the individuality of species. , 1999, Archives of biochemistry and biophysics.

[9]  T. Osborne,et al.  Thyroid Hormone Regulation and Cholesterol Metabolism Are Connected through Sterol Regulatory Element-binding Protein-2 (SREBP-2)* , 2003, Journal of Biological Chemistry.

[10]  P. Edwards,et al.  LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. , 2002, Vascular pharmacology.

[11]  P. Sigler,et al.  Structural determinants of nuclear receptor assembly on DNA direct repeats , 1995, Nature.

[12]  J. Menke,et al.  Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[13]  Yanqiao Zhang,et al.  SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACCalpha transcription in hepatocytes. , 2003, Journal of lipid research.

[14]  M. Lazar Thyroid hormone action: a binding contract. , 2003, The Journal of clinical investigation.

[15]  J. Samarut,et al.  Thyroid hormone receptors: lessons from knockout and knock-in mutant mice , 2003, Trends in Endocrinology & Metabolism.

[16]  N. Lee,et al.  Patterns of liver gene expression governed by TRbeta. , 2002, Molecular endocrinology.

[17]  Y. Chao,et al.  A Novel Liver X Receptor Agonist Establishes Species Differences in the Regulation of Cholesterol 7α-Hydroxylase (CYP7a). , 2002, Endocrinology.

[18]  S. Joseph,et al.  LXRs: new therapeutic targets in atherosclerosis? , 2003, Current opinion in pharmacology.

[19]  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.

[20]  M. Lazar,et al.  The mechanism of action of thyroid hormones. , 2000, Annual review of physiology.

[21]  N. McKenna,et al.  Minireview: Nuclear Receptor Coactivators-An Update. , 2002, Endocrinology.

[22]  H Grøn,et al.  Peptides as tools in drug discovery. , 2000, Current opinion in drug discovery & development.

[23]  J. Gustafsson,et al.  Comparing nuclear receptors in worms, flies and humans. , 2001, Trends in pharmacological sciences.

[24]  T. Scanlan,et al.  Design and synthesis of receptor ligands. , 2003, Methods in enzymology.

[25]  R. Redinger Nuclear receptors in cholesterol catabolism: molecular biology of the enterohepatic circulation of bile salts and its role in cholesterol homeostasis. , 2003, The Journal of laboratory and clinical medicine.

[26]  M. Ravid,et al.  Rosiglitazone (PPARγ‐agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes–atherosclerosis mouse model , 2003, Diabetes, obesity & metabolism.

[27]  Guy Perrière,et al.  Update of NUREBASE: nuclear hormone receptor functional genomics , 2004, Nucleic Acids Res..

[28]  Xiaohong Liu,et al.  Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors , 2003, Nature.

[29]  J. Auwerx,et al.  Expression of the liver X receptor α and β in embryonic and adult mice , 2004 .

[30]  J. Breslow,et al.  Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mices⃞s⃞ The online version of this article (available at http://www.jlr.org) contains one supplemental table. Published, JLR Papers in Press, August 1, 2003. DOI 10.1194/jlr.M300203-JLR200 , 2003, Journal of Lipid Research.

[31]  E. Topol,et al.  Prevalence of Conventional Risk Factors in Patients With Coronary Heart Disease , 2003 .

[32]  W. Wiersinga,et al.  Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver. , 2003, The Journal of endocrinology.

[33]  D. Gewirth,et al.  Structural basis of VDR–DNA interactions on direct repeat response elements , 2002, The EMBO journal.

[34]  X. Hu,et al.  Liver X receptors interact with corepressors to regulate gene expression. , 2003, Molecular endocrinology.

[35]  F. Wondisford,et al.  Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation* , 2003, The Journal of Biological Chemistry.

[36]  Stefan Svensson,et al.  Crystal structure of the heterodimeric complex of LXRα and RXRβ ligand‐binding domains in a fully agonistic conformation , 2003, The EMBO journal.

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

[38]  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.

[39]  L. Jendeberg,et al.  Crystal Structure of the Ligand Binding Domain of the Human Nuclear Receptor PPARγ* , 1998, The Journal of Biological Chemistry.

[40]  N. Mitro,et al.  LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport. , 2004, Biochemical Society transactions.

[41]  Folkert Kuipers,et al.  Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-rich Very Low Density Lipoprotein Particles* , 2002, The Journal of Biological Chemistry.

[42]  D. Vanderwall,et al.  Correlation between in vitro peptide binding profiles and cellular activities for estrogen receptor-modulating compounds. , 2004, Molecular endocrinology.

[43]  L. Bladh,et al.  Pharmacophores incorporating numerous excluded volumes defined by X-ray crystallographic structure in three-dimensional database searching: application to the thyroid hormone receptor. , 1998, Journal of medicinal chemistry.

[44]  Grazia Chiellini,et al.  Ligand selectivity by seeking hydrophobicity in thyroid hormone receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Baxter,et al.  Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in rats and primates: selective actions relative to 3,5,3'-triiodo-L-thyronine. , 2004, Endocrinology.

[46]  J. Auwerx,et al.  Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  B. Desvergne How do thyroid hormone receptors bind to structurally diverse response elements? , 1994, Molecular and Cellular Endocrinology.

[48]  S. Teichmann,et al.  Nuclear Receptors: The Evolution of Diversity , 2004, Science's STKE.

[49]  Y. Chao,et al.  Reduction of Atherosclerosis by the Peroxisome Proliferator-activated Receptor α Agonist Fenofibrate in Mice* , 2002, The Journal of Biological Chemistry.

[50]  T. Pearson,et al.  The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. , 2000, Archives of internal medicine.

[51]  H Grøn,et al.  Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Willson,et al.  The PPARs: from orphan receptors to drug discovery. , 2000, Journal of medicinal chemistry.

[53]  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 .

[54]  Jonathan Greer,et al.  The Three-dimensional Structures of Antagonistic and Agonistic Forms of the Glucocorticoid Receptor Ligand-binding Domain , 2003, Journal of Biological Chemistry.

[55]  R. Fletterick,et al.  A role for helix 3 of the TRβ ligand‐binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone , 1998, The EMBO journal.

[56]  M. Baker,et al.  Evolution of adrenal and sex steroid action in vertebrates: a ligand-based mechanism for complexity. , 2003, Bioessays.

[57]  Ruben Abagyan,et al.  Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Derek Parks,et al.  X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch. , 2003, The Journal of biological chemistry.

[59]  B. Zhang,et al.  Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits. , 2004, Atherosclerosis.

[60]  L. Duntas Thyroid disease and lipids. , 2002, Thyroid : official journal of the American Thyroid Association.

[61]  Minghan Wang,et al.  HDL: the metabolism, function, and therapeutic importance. , 2004, Chemical reviews.

[62]  H. Gronemeyer,et al.  How to finger DNA , 1995, Nature.

[63]  J. W. Thornton Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J. Mckenney,et al.  Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial , 2003, Current medical research and opinion.

[65]  A. Dyer,et al.  Major Risk Factors as Antecedents of Fatal and Nonfatal Coronary Heart Disease Events , 2003 .

[66]  Sherry Sun,et al.  The Three-dimensional Structure of the Liver X Receptor β Reveals a Flexible Ligand-binding Pocket That Can Accommodate Fundamentally Different Ligands* , 2003, Journal of Biological Chemistry.

[67]  R. Collins,et al.  Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions , 2004, The Lancet.

[68]  Richard A Heyman,et al.  Orphan nuclear receptor modulators. , 2003, Current topics in medicinal chemistry.

[69]  Johan Malm,et al.  Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[70]  T. Willson,et al.  The Drosophila Orphan Nuclear Receptor DHR38 Mediates an Atypical Ecdysteroid Signaling Pathway , 2003, Cell.

[71]  David Crews,et al.  Resurrecting the Ancestral Steroid Receptor: Ancient Origin of Estrogen Signaling , 2003, Science.

[72]  W. Dietz,et al.  Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. , 2002, JAMA.

[73]  L. Agellon,et al.  Regulation of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) by thyroid hormone in transgenic mice. , 2004, Endocrinology.

[74]  L. Jendeberg,et al.  Identification of residues in the PXR ligand binding domain critical for species specific and constitutive activation. , 2002, European journal of biochemistry.

[75]  D. Forrest,et al.  Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice. , 2002, Molecular endocrinology.

[76]  W. Wiersinga,et al.  Changes in plasma low-density lipoprotein (LDL)- and high-density lipoprotein cholesterol in hypo- and hyperthyroid patients are related to changes in free thyroxine, not to polymorphisms in LDL receptor or cholesterol ester transfer protein genes. , 2000, The Journal of clinical endocrinology and metabolism.

[77]  Mary E. McGrath,et al.  A structural role for hormone in the thyroid hormone receptor , 1995, Nature.

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

[79]  D. Mangelsdorf,et al.  Liver X receptor signaling pathways in cardiovascular disease. , 2003, Molecular endocrinology.

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

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

[82]  M. Lambert,et al.  Activation of nuclear receptors: a perspective from structural genomics. , 2003, Structure.

[83]  P. Ladenson,et al.  Hypothyroidism and atherosclerosis. , 2003, The Journal of clinical endocrinology and metabolism.