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J. Biol. Chem., Vol. 281, Issue 49, 37603-37615, December 8, 2006

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Aberrant Hepatic Expression of PPAR2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis^*

Yuan-Li Zhang¹, Antonio Hernandez-Ono¹, Patty Siri, Stuart Weisberg, Donna Conlon, Mark J. Graham, Rosanne M. Crooke, Li-Shin Huang, and Henry N. Ginsberg²

From the Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032 and ISIS Pharmaceuticals, Carlsbad, California 92672

Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064-46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPAR2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPAR, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPAR antisense oligonucleotide resulted in dramatic reductions of both PPAR1 and PPAR2 mRNA, PPAR2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPAR2. The mechanism whereby hepatic Ppar2 gene expression is increased and how PPAR2 stimulates lipogenesis is under investigation.

Received for publication, May 17, 2006 , and in revised form, September 6, 2006.

^* This work was supported by National Institutes of Health Grants NHLBI HL55368, HL73030 (to H. N. G.), and HL62583 (to L.-S. H.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, PH 10-305, Columbia University, 630 West 168th St., New York, NY 10032. Tel.: 212-305-9562; Fax: 212-305-3213; E-mail: hng1{at}columbia.edu.

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