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Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice

¹Translational Metabolism Unit, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine; ²United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine; ³Endocrine Service, Ben Taub General Hospital, Houston, Texas; ⁴Division of Engineering and Physical Sciences, Office of Research Sciences, ⁵Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases and ⁶Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; ⁷University of Colorado Health Sciences Center, Denver, Colorado; ⁸Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Bavaria; and ⁹Institute of Biochemistry, Humboldt University, Berlin, Germany

Submitted 5 April 2006 ; accepted in final form 11 July 2006

HIV infection is associated with abnormal lipid metabolism, body fat redistribution, and altered energy expenditure. The pathogenesis of these complex abnormalities is unclear. Viral protein R (Vpr), an HIV-1 accessory protein, can regulate gene transcription mediated by the glucocorticoid receptor and peroxisome proliferator-activated receptor- and affect mitochondrial function in vitro. To test the hypothesis that expression of Vpr in liver and adipocytes can alter lipid metabolism in vivo, we engineered mice to express Vpr under control of the phosphoenolpyruvate carboxykinase promoter in a tissue-specific and inducible manner and investigated the effects of dietary fat, indinavir, and dexamethasone on energy metabolism and body composition. The transgenic mice expressed Vpr mRNA in white and brown adipose tissues and liver and immunoaffinity capillary electrophoresis revealed that they had free Vpr protein in the plasma. Compared with wild-type (WT) animals, Vpr mice had lower plasma triglyceride levels after 6 wk (P < 0.05) but not after 10 wk of a high-fat diet and lower plasma cholesterol levels after 10 wk of high-fat diet (P < 0.05). Treatment with dexamethasone obviated group differences, whereas indinavir had no significant independent effect on lipids. In the fasted state, Vpr mice had a higher respiratory quotient than WT mice (P < 0.05). These data provide the first in vivo evidence that HIV-1 Vpr expressed at low levels in adipose tissues and liver can 1) circulate in the blood, 2) regulate lipid and fatty acid metabolism, and 3) alter fuel selection for oxidation in the fasted state.

human immunodeficiency virus lipodystrophy; glucose; triglycerides; cholesterol; energy expenditure; fat oxidation