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J. Biol. Chem., Vol. 279, Issue 23, 24427-24434, June 4, 2004

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Transcription Coactivator PBP, the Peroxisome Proliferator-activated Receptor (PPAR)-binding Protein, Is Required for PPAR-regulated Gene Expression in Liver^*

Yuzhi Jia, Chao Qi, Papreddy Kashireddi, Sailesh Surapureddi, Yi-Jun Zhu, M. Sambasiva Rao, Derek Le Roith, Pierre Chambon¶, Frank J. Gonzalez||, and Janardan K. Reddy**

From the Department of Pathology, Northwestern University, Feinberg School of Medicine, Illinois 60611-3008, Diabetes Branch, National Institutes of Health, Bethesda, Maryland 20892, ^¶Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/Universite Louis Pasteur, College de France, BP 10142, 67404 Illkirch, France, and ^||Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892

Nuclear receptor coactivator PBP (peroxisome proliferator-activated receptor (PPAR)-binding protein) functions as a coactivator for PPARs and other nuclear receptors. PBP serves as an anchor for TRAP (thyroid hormone receptor-associated proteins)/mediator multisubunit cofactor transcription complex. Disruption of the PBP/TRAP220 gene results in embryonic lethality around embryonic day 11.5 by affecting placental, cardiac, hepatic, and bone marrow development. Because PPAR isoforms , , and / function as important regulators of lipid homeostasis in mammals, it becomes important to assess the requirement of coactivator PBP in the regulation of PPAR functions in vivo. Sustained activation of PPAR by structurally diverse classes of chemicals of biological importance, designated peroxisome proliferators, leads to proliferation of peroxisomes in liver, induction of PPAR target genes including those involved in fatty acid oxidation, and the eventual development of liver tumors. Here, we show that targeted deletion of PBP in liver parenchymal cells, using the Cre-loxP system, results in the near abrogation of PPAR ligand-induced peroxisome proliferation and liver cell proliferation, as well as the induction of PPAR-regulated genes in PBP-deficient liver cells. In contrast, scattered PBP^+/+ hepatocytes in these livers showed DNA synthesis and were markedly hypertrophic with peroxisome proliferation in response to PPAR ligands. Chromatin immunoprecipitation data suggest that in PBP conditional null livers, there appears to be reduced association of cofactors, especially of CBP and TRAP150, to the mouse enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase gene promoter. These observations suggest that PBP is required for the stabilization of multiprotein cofactor complexes. In essence, the absence of PBP in hepatocytes in vivo appears to mimic the absence of PPAR, indicating that coactivator PBP is essential for PPAR-regulated gene expression in liver parenchymal cells.

Received for publication, March 3, 2004

^* This work was supported by National Institutes of Health Grants GM23750 and CA104578. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Pathology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611-3008. Tel.: 312-503-8144; Fax: 312-503-8249; E-mail: jkreddy{at}northwestern.edu.

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