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J. Biol. Chem., Vol. 283, Issue 19, 13087-13099, May 9, 2008

This Article Free via Author's Choice: AC AC Full Text Full Text (PDF) Supplemental Data AC All Versions of this Article: 283/19/13087    most recent M800533200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Reid, B. N. Articles by Huang, L.-S. PubMed PubMed Citation Articles by Reid, B. N. Articles by Huang, L.-S. Social Bookmarking                      What's this?

Hepatic Overexpression of Hormone-sensitive Lipase and Adipose Triglyceride Lipase Promotes Fatty Acid Oxidation, Stimulates Direct Release of Free Fatty Acids, and Ameliorates Steatosis^*

Brendan N. Reid, Gene P. Ables¹, Oleg A. Otlivanchik, Gabriele Schoiswohl, Rudolf Zechner², William S. Blaner, Ira J. Goldberg, Robert F. Schwabe, Streamson C. Chua, Jr.^¶, and Li-Shin Huang³

From the Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, the Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria, and the ^¶Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461

Hepatic steatosis is often associated with insulin resistance and obesity and can lead to steatohepatitis and cirrhosis. In this study, we have demonstrated that hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tissues, also contribute to lipolysis in the liver and can mobilize hepatic triglycerides in vivo and in vitro. Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40–60% in both ob/ob mice and mice with high fat diet-induced obesity. However, these enzymes did not affect fasting plasma triglyceride and free fatty acid levels or triglyceride and apolipoprotein B secretion rates. Plasma 3-β-hydroxybutyrate levels were increased 3–5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in β-oxidation. Expression of genes involved in fatty acid transport and synthesis, lipid storage, and mitochondrial bioenergetics was unchanged. Mechanistic studies in oleate-supplemented McA-RH7777 cells with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be attributed to increases in β-oxidation as well as direct release of free fatty acids into the medium. In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct release of free fatty acid, and ameliorate hepatic steatosis. This study suggests a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these enzymes as potential therapeutic targets for ameliorating hepatic steatosis associated with insulin resistance and obesity.

Received for publication, January 22, 2008 , and in revised form, March 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL62583 (to L. S. H.), DK079221 (to W. S. B.), HL73029, HL45095 (to I. J. G.), and DK063306 (to S. C. C.). 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. 1–3.

¹ Recipient of National Institutes of Health T32 Training Grant HL007343.

² Supported by Genome Research in Austria funded by the Austrian Ministry of Science and Research and F3002 funded by the Austrian Science Fund.

³ To whom correspondence should be addressed: Columbia University, College of Physicians & Surgeons, 630 W. 168th St., P&S 9-503, NY, New York 10032. Tel.: 212-305-9594; Fax: 212-305-3213; E-mail: lh99{at}columbia.edu.

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