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J. Biol. Chem., Vol. 283, Issue 17, 11633-11644, April 25, 2008

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Apolipoprotein AII Is a Regulator of Very Low Density Lipoprotein Metabolism and Insulin Resistance^*

Lawrence W. Castellani¹, Cara N. Nguyen, Sarada Charugundla, Michael M. Weinstein, Chau X. Doan, William S. Blaner, Nuttaporn Wongsiriroj, and Aldons J. Lusis^¶||**

From the Departments of Medicine/Cardiology University of California, Los Angeles, Los Angeles, California 90095, the Department of Medicine, Columbia University, New York, New York 10032, and the Departments of ^¶Microbiology, Immunology, and Molecular Genetics and ^||Human Genetics, and the ^**Molecular Biology Institute, University of California, Los Angeles, California 90095

Apolipoprotein AII (apoAII) transgenic (apoAIItg) mice exhibit several traits associated with the insulin resistance (IR) syndrome, including IR, obesity, and a marked hypertriglyceridemia. Because treatment of the apoAIItg mice with rosiglitazone ameliorated the IR and hypertriglyceridemia, we hypothesized that the hypertriglyceridemia was due largely to overproduction of very low density lipoprotein (VLDL) by the liver, a normal response to chronically elevated insulin and glucose. We now report in vivo and in vitro studies that indicate that hepatic fatty acid oxidation was reduced and lipogenesis increased, resulting in a 25% increase in triglyceride secretion in the apoAIItg mice. In addition, we observed that hydrolysis of triglycerides from both chylomicrons and VLDL was significantly reduced in the apoAIItg mice, further contributing to the hypertriglyceridemia. This is a direct, acute effect, because when mouse apoAII was injected into mice, plasma triglyceride concentrations were significantly increased within 4 h. VLDL from both control and apoAIItg mice contained significant amounts of apoAII, with 4 times more apoAII on apoAIItg VLDL. ApoAII was shown to transfer spontaneously from high density lipoprotein (HDL) to VLDL in vitro, resulting in VLDL that was a poorer substrate for hydrolysis by lipoprotein lipase. These results indicate that one function of apoAII is to regulate the metabolism of triglyceride-rich lipoproteins, with HDL serving as a plasma reservoir of apoAII that is transferred to the triglyceride-rich lipoproteins in much the same way as VLDL and chylomicrons acquire most of their apoCs from HDL.

Received for publication, November 1, 2007 , and in revised form, December 21, 2007.

^* This work was supported by National Institutes of Health Grants HL28481 and DK071673. 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 To whom correspondence should be addressed: Dept. of Medicine, Div. of Cardiology, BH-307 CHS, University of California, Los Angeles, CA 90095. Tel.: 310-825-5778; Fax: 310-794-7345; E-mail: lcastellani{at}mednet.ucla.edu.

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