This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this book Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kliewer, S. A. Articles by Willson, T. M. Search for Related Content PubMed PubMed Citation Articles by Kliewer, S. A. Articles by Willson, T. M.

Peroxisome Proliferator-Activated Receptors

From Genes to Physiology

Glaxo Wellcome, Inc., 5 Moore Drive, Research Triangle Park, North Carolina 27709

ABSTRACT

The peroxisome proliferator-activated receptors (PPAR, , ) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPAR (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPAR agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPAR (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPAR and PPAR, relatively little is known about the biology of PPAR (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.

This article has been cited by other articles:

				K. R. Feingold, Y. Wang, A. Moser, J. K. Shigenaga, and C. Grunfeld LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney J. Lipid Res., October 1, 2008; 49(10): 2179 - 2187. [Abstract] [Full Text] [PDF]

				D. C. Chan, G. F. Watts, E. M.M. Ooi, J. Ji, A. G. Johnson, and P. H. R. Barrett Atorvastatin and Fenofibrate Have Comparable Effects on VLDL-Apolipoprotein C-III Kinetics in Men With the Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1831 - 1837. [Abstract] [Full Text] [PDF]

				T. Reinehr, B. Stoffel-Wagner, and C. L. Roth Retinol-Binding Protein 4 and Its Relation to Insulin Resistance in Obese Children before and after Weight Loss J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2287 - 2293. [Abstract] [Full Text] [PDF]

				V Costa, D Foti, F Paonessa, E Chiefari, L Palaia, G Brunetti, E Gulletta, A Fusco, and A Brunetti The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and thiazolidinedione-PPAR{gamma} agonists Endocr. Relat. Cancer, March 1, 2008; 15(1): 325 - 335. [Abstract] [Full Text] [PDF]

				H. Wang, L. Qiang, and S. R. Farmer Identification of a Domain within Peroxisome Proliferator-Activated Receptor {gamma} Regulating Expression of a Group of Genes Containing Fibroblast Growth Factor 21 That Are Selectively Repressed by SIRT1 in Adipocytes Mol. Cell. Biol., January 1, 2008; 28(1): 188 - 200. [Abstract] [Full Text] [PDF]

				I. Aeberli, R. Biebinger, R. Lehmann, D. l'Allemand, G. A. Spinas, and M. B. Zimmermann Serum Retinol-Binding Protein 4 Concentration and Its Ratio to Serum Retinol Are Associated with Obesity and Metabolic Syndrome Components in Children J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4359 - 4365. [Abstract] [Full Text] [PDF]

				C. R. Bush, J. M. Havens, B. M. Necela, W. Su, L. Chen, M. Yanagisawa, P. Z. Anastasiadis, R. Guerra, B. A. Luxon, and E. A. Thompson Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor {gamma} and Calcium Signaling in Human Colorectal Cancer Cells J. Biol. Chem., August 10, 2007; 282(32): 23387 - 23401. [Abstract] [Full Text] [PDF]

				J. M. Hall and D. P. McDonnell The Molecular Mechanisms Underlying the Proinflammatory Actions of Thiazolidinediones in Human Macrophages Mol. Endocrinol., August 1, 2007; 21(8): 1756 - 1768. [Abstract] [Full Text] [PDF]

				R. Coras, A. Holsken, S. Seufert, J. Hauke, I. Y. Eyupoglu, M. Reichel, C. Trankle, F. A. Siebzehnrubl, R. Buslei, I. Blumcke, et al. The peroxisome proliferator-activated receptor-{gamma} agonist troglitazone inhibits transforming growth factor-{beta}-mediated glioma cell migration and brain invasion Mol. Cancer Ther., June 1, 2007; 6(6): 1745 - 1754. [Abstract] [Full Text] [PDF]

				A. M. Sharma and B. Staels Peroxisome Proliferator-Activated Receptor {gamma} and Adipose Tissue--Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 386 - 395. [Abstract] [Full Text] [PDF]

				L. Xu, C. Han, and T. Wu A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor-{delta} and Prostaglandin E2 Signaling Pathways for Human Cholangiocarcinoma Cell Growth J. Biol. Chem., November 10, 2006; 281(45): 33982 - 33996. [Abstract] [Full Text] [PDF]

				J. Liu, H. Wang, Y. Zuo, and S. R. Farmer Functional Interaction between Peroxisome Proliferator-Activated Receptor {gamma} and {beta}-Catenin Mol. Cell. Biol., August 1, 2006; 26(15): 5827 - 5837. [Abstract] [Full Text] [PDF]

				T. Harrity, D. Farrelly, A. Tieman, C. Chu, L. Kunselman, L. Gu, R. Ponticiello, M. Cap, F. Qu, C. Shao, et al. Muraglitazar, a Novel Dual ({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves {beta}-Cell Function in db/db Mice Diabetes, January 1, 2006; 55(1): 240 - 248. [Abstract] [Full Text] [PDF]

				T. M. D'Eon, S. C. Souza, M. Aronovitz, M. S. Obin, S. K. Fried, and A. S. Greenberg Estrogen Regulation of Adiposity and Fuel Partitioning: EVIDENCE OF GENOMIC AND NON-GENOMIC REGULATION OF LIPOGENIC AND OXIDATIVE PATHWAYS J. Biol. Chem., October 28, 2005; 280(43): 35983 - 35991. [Abstract] [Full Text] [PDF]

				E.C. Tok, A. Aktas, D. Ertunc, E.M. Erdal, and S. Dilek Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-{gamma}2 Pro12Ala genotype Hum. Reprod., June 1, 2005; 20(6): 1590 - 1595. [Abstract] [Full Text] [PDF]

				H. Noushmehr, E. D'Amico, L. Farilla, H. Hui, K. A. Wawrowsky, W. Mlynarski, A. Doria, N. A. Abumrad, and R. Perfetti Fatty Acid Translocase (FAT/CD36) Is Localized on Insulin-Containing Granules in Human Pancreatic {beta}-Cells and Mediates Fatty Acid Effects on Insulin Secretion Diabetes, February 1, 2005; 54(2): 472 - 481. [Abstract] [Full Text] [PDF]

				N. Balasubramaniyan, M. Shahid, F. J. Suchy, and M. Ananthanarayanan Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development Am J Physiol Gastrointest Liver Physiol, February 1, 2005; 288(2): G251 - G260. [Abstract] [Full Text] [PDF]

				J. M. Huss and D. P. Kelly Nuclear Receptor Signaling and Cardiac Energetics Circ. Res., September 17, 2004; 95(6): 568 - 578. [Abstract] [Full Text] [PDF]

				P. Ferre The Biology of Peroxisome Proliferator-Activated Receptors: Relationship With Lipid Metabolism and Insulin Sensitivity Diabetes, February 1, 2004; 53(90001): S43 - 50. [Abstract] [Full Text]

				J. Kaput and R. L. Rodriguez Nutritional genomics: the next frontier in the postgenomic era Physiol Genomics, January 15, 2004; 16(2): 166 - 177. [Abstract] [Full Text] [PDF]

				U. Dressel, T. L. Allen, J. B. Pippal, P. R. Rohde, P. Lau, and G. E. O. Muscat The Peroxisome Proliferator-Activated Receptor {beta}/{delta} Agonist, GW501516, Regulates the Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal Muscle Cells Mol. Endocrinol., December 1, 2003; 17(12): 2477 - 2493. [Abstract] [Full Text] [PDF]

				C. H. Hurst and D. J. Waxman Activation of PPAR{alpha} and PPAR{gamma} by Environmental Phthalate Monoesters Toxicol. Sci., August 1, 2003; 74(2): 297 - 308. [Abstract] [Full Text] [PDF]

				J. M. Maglich, J. A. Caravella, M. H. Lambert, T. M. Willson, J. T. Moore, and L. Ramamurthy The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily Nucleic Acids Res., July 15, 2003; 31(14): 4051 - 4058. [Abstract] [Full Text] [PDF]

				C. Dello Russo, V. Gavrilyuk, G. Weinberg, A. Almeida, J. P. Bolanos, J. Palmer, D. Pelligrino, E. Galea, and D. L. Feinstein Peroxisome Proliferator-activated Receptor gamma Thiazolidinedione Agonists Increase Glucose Metabolism in Astrocytes J. Biol. Chem., February 14, 2003; 278(8): 5828 - 5836. [Abstract] [Full Text] [PDF]

				Y.-J. Y. Wan, G. Han, Y. Cai, T. Dai, T. Konishi, and A.-S. Leng Hepatocyte Retinoid X Receptor-{alpha}-Deficient Mice Have Reduced Food Intake, Increased Body Weight, and Improved Glucose Tolerance Endocrinology, February 1, 2003; 144(2): 605 - 611. [Abstract] [Full Text] [PDF]

				Z.-C. Dang, V. Audinot, S. E. Papapoulos, J. A. Boutin, and C. W. G. M. Lowik Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) as a Molecular Target for the Soy Phytoestrogen Genistein J. Biol. Chem., January 3, 2003; 278(2): 962 - 967. [Abstract] [Full Text] [PDF]

				J. A. Copland, P. J. Davies, G. L. Shipley, C. G. Wood, B. A. Luxon, and R. J. Urban The Use of DNA Microarrays to Assess Clinical Samples: The Transition from Bedside to Bench to Bedside Recent Prog. Horm. Res., January 1, 2003; 58(1): 25 - 53. [Abstract] [Full Text] [PDF]

				S. H. Lee and K. L. Hossner Coordinate regulation of ovine adipose tissue gene expression by propionate J Anim Sci, November 1, 2002; 80(11): 2840 - 2849. [Abstract] [Full Text] [PDF]

				G. D. Snyder, U. M. Krishna, J. R. Falck, and A. A. Spector Evidence for a membrane site of action for 14,15-EET on expression of aromatase in vascular smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1936 - H1942. [Abstract] [Full Text] [PDF]

				H. N. Ginsberg New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism Circulation, October 15, 2002; 106(16): 2137 - 2142. [Full Text] [PDF]

				L. A. Cowart, S. Wei, M.-H. Hsu, E. F. Johnson, M. U. Krishna, J. R. Falck, and J. H. Capdevila The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands J. Biol. Chem., September 13, 2002; 277(38): 35105 - 35112. [Abstract] [Full Text] [PDF]

				D. M. Muoio, P. S. MacLean, D. B. Lang, S. Li, J. A. Houmard, J. M. Way, D. A. Winegar, J. C. Corton, G. L. Dohm, and W. E. Kraus Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) alpha Knock-out Mice. EVIDENCE FOR COMPENSATORY REGULATION BY PPARdelta J. Biol. Chem., July 12, 2002; 277(29): 26089 - 26097. [Abstract] [Full Text] [PDF]

				C. J. Sinal, M. Yoon, and F. J. Gonzalez Antagonism of the Actions of Peroxisome Proliferator-activated Receptor-alpha by Bile Acids J. Biol. Chem., December 7, 2001; 276(50): 47154 - 47162. [Abstract] [Full Text] [PDF]

				Y. Barak, D. Liao, W. He, E. S. Ong, M. C. Nelson, J. M. Olefsky, R. Boland, and R. M. Evans Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer PNAS, January 8, 2002; 99(1): 303 - 308. [Abstract] [Full Text] [PDF]