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J. Biol. Chem., Vol. 278, Issue 35, 32702-32709, August 29, 2003

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Transgenic Mice Expressing Lipoprotein Lipase in Adipose Tissue

ABSENCE OF THE PROXIMAL 3'-UNTRANSLATED REGION CAUSES TRANSLATIONAL UPREGULATION^*

Lori L. Hensley , Gouri Ranganathan , Elke M. Wagner , Brian D. Wells , Joseph C. Daniel , Diane Vu , Clay F. Semenkovich ¶, Rudolf Zechner  and Philip A. Kern  ||

From the The Central Arkansas Veterans HealthCare System, and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, the Institute of Molecular Biology, Biochemistry, and Microbiology, Karl-Franzens-University, Graz, Austria, and the ^¶Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and adipocyte metabolism. Defects in LPL can lead to hypertriglyceridemia and the subsequent development of atherosclerosis. The mechanisms of regulation of this enzyme are complex and may occur at multiple levels of gene expression. Because the 3'-untranslated region (UTR) is involved in LPL translational regulation, transgenic mice were generated with adipose tissue expression of an LPL construct either with or without the proximal 3'-UTR and driven by the aP2 promoter. Both transgenic mouse colonies were viable and expressed the transgene, resulting in a 2-fold increase in LPL activity in white adipose tissue. Neither mouse colony exhibited any obvious phenotype in terms of body weight, plasma lipids, glucose, and non-esterified fatty acid levels. In the mice expressing hLPL with an intact 3'-UTR, hLPL mRNA expression approximately paralleled hLPL activity. However in the mice without the proximal 3'-UTR, hLPL mRNA was low in the setting of large amounts of hLPL protein and LPL activity. In previous studies, the 3'-UTR of LPL was critical for the inhibitory effects of constitutively expressed hormones, such as thyroid hormone and catecholamines. Therefore, these data suggest that the absence of the 3'-UTR results in a translationally unrepressed LPL, resulting in a moderate overexpression of adipose LPL activity.

Received for publication, April 22, 2003 , and in revised form, June 3, 2003.

^* This work was supported in part by a Career Development Award from the American Diabetes Association, DK 39176 and HL 58427 from the National Institutes of Health, a Merit Review Grant from the Veterans Administration, and the Austrian FWF Grants FWF-701 and FWF-713. 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.

^|| To whom correspondence should be addressed: 151LR, Central Arkansas Veterans Healthcare System, 4300 W. 7^th St., Little Rock, AR 72205. Tel.: 501-257-4816; Fax: 501-257-4821; E-mail: kernphilipa{at}uams.edu.

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