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J. Biol. Chem., Vol. 281, Issue 21, 14683-14690, May 26, 2006

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Partnership of PGC-1 and HNF4 in the Regulation of Lipoprotein Metabolism^*

James Rhee, Hongfei Ge, Wenli Yang, Melina Fan, Christoph Handschin, Marcus Cooper, Jiandie Lin¹, Cai Li², and Bruce M. Spiegelman³

From the Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and the Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390

Peroxisome proliferator-activated receptor coactivator-1 (PGC-1) is a transcriptional coactivator involved in several aspects of energy metabolism. It is induced or activated under different stimuli in a highly tissue-specific manner and subsequently partners with certain transcription factors in those tissues to execute various biological programs. In the fasted liver, PGC-1 is induced and interacts with hepatocyte nuclear factor 4 (HNF4) and other transcription factors to activate gluconeogenesis and increase hepatic glucose output. Given the broad spectrum of liver genes responsive to HNF4, we sought to determine those that were specifically targeted by the combination of PGC-1 and HNF4. Coexpression of these two molecules in murine stem cells reveals a high induction of mRNA for apolipoproteins A-IV and C-II. Forced expression of PGC-1 in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III. Coactivation of the apoC-III/A-IV promoter region by PGC-1 occurs through a highly conserved HNF4 response element, the loss of which completely abolishes activation by PGC-1 and HNF4. Adenoviral infusion of PGC-1 into live mice increases hepatic expression of apolipoproteins A-IV, C-II, and C-III and increases serum and very low density lipoprotein triglyceride levels. Conversely, knock down of PGC-1 in vivo causes a decrease in both apolipoprotein expression and serum triglyceride levels. These data point to a crucial role for the PGC-1/HNF4 partnership in hepatic lipoprotein metabolism.

Received for publication, November 28, 2005 , and in revised form, March 27, 2006.

^* This work was supported by NIDDK, National Institutes of Health Grants DK54477 and DK61562 (to B. M. S.). 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 and S2 and supplemental Tables S1–S3.

¹ Present address: Life Science Inst., University of Michigan, Ann Arbor, MI 48109.

² Present address: Dept. of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065.

³ To whom correspondence should be addressed: Dana-Farber Cancer Inst., One Jimmy Fund Way, Boston, MA 02115. Tel.: 617-632-3567; Fax: 617-632-4655; E-mail: bruce_spiegelman{at}dfci.harvard.edu.

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