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J. Biol. Chem., Vol. 282, Issue 50, 36766-36776, December 14, 2007

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Induction of Nuclear Translocation of Constitutive Androstane Receptor by Peroxisome Proliferator-activated Receptor Synthetic Ligands in Mouse Liver^*

Dongsheng Guo, Joy Sarkar, Kelly Suino-Powell, Yong Xu, Kojiro Matsumoto, Yuzhi Jia, Songtao Yu, Sonal Khare, Kasturi Haldar, M. Sambasiva Rao, Jennifer E. Foreman^¶, Satdarshan P. S. Monga^||, Jeffrey M. Peters^¶, H. Eric Xu, and Janardan K. Reddy¹

From the Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008, Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, ^¶Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, and the ^||Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261

Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor (PPAR) and enhance the transcription of several genes in liver. We report here that synthetic PPAR ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adenoviral-enhanced green fluorescent protein-CAR expression demonstrated that PPAR synthetic ligands drive CAR into the hepatocyte nucleus in a PPAR- and PPARβ-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPAR ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPAR ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPAR ligands not only serve as PPAR agonists but possibly act as CAR antagonists.

Received for publication, August 27, 2007 , and in revised form, October 25, 2007.

^* This work was supported by the National Institutes of Health Grants GM23750 (to J. K. R.) and CA104578 (to J. K. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ To whom correspondence should be addressed: Dept. of Pathology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611-3008. Tel.: 312-503-7948; Fax: 312-503-8249; E-mail: jkreddy{at}northwestern.edu.

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