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J. Biol. Chem., Vol. 281, Issue 21, 15013-15020, May 26, 2006

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A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway^*

Jie Zhou, Yonggong Zhai, Ying Mu¹, Haibiao Gong², Hirdesh Uppal, David Toma, Songrong Ren, Ronald M. Evans³, and Wen Xie⁴

From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92122

The pregnane X receptor (PXR) was isolated as a xenosensor regulating xenobiotic responses. In this study, we show that PXR plays an endobiotic role by impacting lipid homeostasis. Expression of an activated PXR in the livers of transgenic mice resulted in an increased hepatic deposit of triglycerides. This PXR-mediated lipid accumulation was independent of the activation of the lipogenic transcriptional factor SREBP-1c (sterol regulatory element-binding protein 1c) and its primary lipogenic target enzymes, including fatty-acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC-1). Instead, the lipid accumulation in transgenic mice was associated with an increased expression of the free fatty acid transporter CD36 and several accessory lipogenic enzymes, such as stearoyl-CoA desaturase-1 (SCD-1) and long chain free fatty acid elongase. Studies using transgenic and knock-out mice showed that PXR is both necessary and sufficient for Cd36 activation. Promoter analyses revealed a DR-3-type of PXR-response element in the mouse Cd36 promoter, establishing Cd36 as a direct transcriptional target of PXR. The hepatic lipid accumulation and Cd36 induction were also seen in the hPXR "humanized" mice treated with the hPXR agonist rifampicin. The activation of PXR was also associated with an inhibition of pro--oxidative genes, such as peroxisome proliferator-activated receptor (PPAR) and thiolase, and an up-regulation of PPAR, a positive regulator of CD36. The cross-regulation of CD36 by PXR and PPAR suggests that this fatty acid transporter may function as a common target of orphan nuclear receptors in their regulation of lipid homeostasis.

Received for publication, October 12, 2005 , and in revised form, March 23, 2006.

^* This work was supported in part by National Institutes of Health Grants ES012479 and CA107011. 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.

¹ Supported by National Institutes of Health International Postdoctoral Fellowship AT002029 [GenBank] .

² Supported by Susan G. Komen Breast Cancer Foundation Postdoctoral Fellowship PDF053458.

³ Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and March of Dimes Chair in Molecular and Developmental Biology.

⁴ To whom correspondence should be addressed. Tel.: 412-648-9941; Fax: 412-648-1664; E-mail: wex6{at}pitt.edu.

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