Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/11/2006
Publication Date: 1/8/2007
Citation: Balasubramanyam, A., Mersmann, H., Jahoor, F., Phillips, T.M., Sekhar, R.V., Schubert, U., Brar, B., Iyer, D., Smith, E.O., Takahashi, H., Lu, H., Anderson, P., Kino, T., Henklein, P., Kopp, J.B. 2007. Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice. American Journal of Physiology - Endocrinology and Metabolism. 292(1):E40-E48. Interpretive Summary: When people are infected with HIV the way their bodies handle fat changes leads to high levels of fat and cholesterol in their blood. The way they use fat for energy also changes. It is important to know what causes these changes because it can lead to early heart disease. In this study we wanted to find out whether a protein made by HIV called Vpr is responsible for these fat changes. We made some special mice that manufactured a lot of Vpr in their bodies and compared them to normal mice. We found that mice that made a lot of Vpr altered the way they handled fat in their bodies and also how they used fat for energy production.
Technical Abstract: 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-gamma 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.