PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth

Abstract

peroxisome proliferator-activated receptor retinoid X receptor, PPRE, peroxisome proliferator-activated receptor response element nuclear hormone receptor thiazolidinedione phosphoenolpyruvate carboxykinase embryonic stem cells 15-hydroxyeicosatetraenoic acid 13-hydroxyoctadecadienoic acid CCAAT/enhancer-binding protein CREB-binding protein histone acetyltransferase tumor necrosis factor-α interleukin-6 liver X receptor The peroxisome proliferator-activated receptors (PPARs)1 comprise an important subfamily of the nuclear hormone receptor (NHR) superfamily. These ligand-activated transcription factors have been intensively studied for more than a decade and have been implicated in such diverse pathways as lipid and glucose homeostasis, control of cellular proliferation, and differentiation. The name PPAR derives from the initial cloning of one isoform as a target of various xenobiotic compounds that were observed to induce proliferation of peroxisomes in the liver (1Issemann I. Green S. Nature. 1990; 347: 645-650Crossref PubMed Scopus (3022) Google Scholar). This protein was called the peroxisome proliferator-activated receptor, now known as PPARα. Within a few years, the group of PPARs was expanded to include PPARγ and PPARδ (also referred to as PPARβ, NUC1, and FAAR) (2Dreyer C. Krey G. Keller H. Givel F. Helftenbein G. Wahli W. Cell. 1992; 68: 879-887Abstract Full Text PDF PubMed Scopus (1195) Google Scholar, 3Desvergne B. Wahli W. Endocr. Rev. 1999; 20: 649-688Crossref PubMed Scopus (2708) Google Scholar, 4Kliewer S.A. Forman B.M. Blumberg B. Ong E.S. Borgmeyer U. Mangelsdorf D.J. Umesono K. Evans R.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7355-7359Crossref PubMed Scopus (1269) Google Scholar, 5Zhu Y. Alvares K. Huang Q. Rao M.S. Reddy J.K. J. Biol. Chem. 1993; 268: 26817-26820Abstract Full Text PDF PubMed Google Scholar, 6Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (1983) Google Scholar). This review will focus on PPARγ.How Do PPARs Work at the Molecular Level?PPARs possess the canonical domain structure of other NHR superfamily members (see Fig. 1). This includes a poorly characterized N-terminal region that contains a potential trans-activation function known as AF-1, followed by a DNA binding domain that includes two zinc fingers. At the carboxyl terminus is a dimerization and ligand binding domain that molecular modeling reveals to be a large hydrophobic pocket and which contains a key, ligand-dependent trans-activation function called AF-2 (7Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Nature. 1998; 395: 137-143Crossref PubMed Scopus (1661) Google Scholar,8Xu H.E. Lambert M.H. Montana V.G. Parks D.J. Blanchard S.G. Brown P.J. Sternbach D.D. Lehmann J.M. Wisely G.B. Willson T.M. Kliewer S.A. Milburn M.V. Mol Cell. 1999; 3: 397-403Abstract Full Text Full Text PDF PubMed Scopus (956) Google Scholar). PPARs bind to cognate DNA elements called PPAR response elements (PPREs) in the 5′-flanking region of target genes. Like many other NHRs, they bind DNA as obligate heterodimers by partnering with one of the retinoid X receptors (RXRs). Known PPREs are direct repeats of an by a of the on the PPRE, with the PPAR binding to the of the C. A. Wahli W. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Kurokawa R. M.H. S. A. Rosenfeld M.G. Glass C.K. Cell. Biol. PubMed Scopus Google Scholar). more than one PPAR which the of are a of the response the of and of other NHRs, with a of nuclear known as and which the and the and which and of which include members of the and are for and many transcription are known for one NHR been in G. J.K. S. Spiegelman B.M. J. 1999; PubMed Scopus Google Scholar, S. C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). possess histone acetyltransferase to the transcription of histone is to the structure of the the to bind and the to target C. PubMed Scopus Google Scholar, Cell. 1999; Full Text Full Text PDF PubMed Scopus Google the by is the intensively studied PPAR have that receptor in pathways of and such as and PPARγ in two protein that are by and at the of the contains at the terminus with P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. Genes Dev. 1994; 8: 1224-1234Crossref PubMed Scopus (1983) Google Scholar). many a of is and is at in that of in many and (see been in to an ligand for of and have been to bind to PPARγ with that in the of target cells are to be for to be have been to bind and PPARγ with J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, K. W. G. Brown J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for to PPARγ with a in the and PPARγ target at at B.M. P. J. Spiegelman B.M. Evans R.M. Cell. Full Text PDF PubMed Scopus Google Scholar, S.A. J.M. Willson T.M. I. Lehmann J.M. Cell. Full Text PDF PubMed Scopus Google Scholar). been to a