One of the long-term goals of our research group is to understand the pathogenesis of HIV associated peripheral subcutaneous (SC) fat wasting (lipoatrophy) and to identify effective preventive and treatment modalities for this syndrome. Recent studies suggest a link between the use of nucleoside reverse transcriptase inhibitors (NRTIs), depletion of SC adipose tissue mitochondrial DNA (mtDNA) as well as decreased levels of oxidative phosphorylation (OXPHOS) subnit components, and the development of lipoatrophy. While this is suggestive of NRTI-mediated mitochondrial toxicity as one contributing factor in the development of lipoatrophy, the specific underlying pathophysiologic mechanisms whereby NRTIs mediate this loss of fat tissue are not well understood. We hypothesize that decrease in mtDNA and/or changes in OXPHOS enzyme activities lead to a decrease in adenosine triphosphate (ATP) production in SC adipocytes from lipoatrophic HIV+ subjects on NRTI-containing medications and that such ATP depletion in turn plays a key role in the development of lipoatrophy by the induction of adipocyte apoptosis. We propose to examine these hypotheses by assaying and comparing ATP production by bioluminescence quantitatively in SC adipocytes from HIV+ subjects with lipoatrophy (n=l 1) and from 3 different control groups: HIV+ subjects without lipoatrophy (n=l 1), HIV+ antiretroviral naive subjects (n=l 1), and HIV seronegative subjects (n=l 1). Obtained ATP levels will be correlated with level of adipocyte apoptosis as well as with adipocyte mtDNA copies/cell by real-time PCR and SC adipose tissue expression of select oxidative phosphorylation (OXPHOS) genes.
| Shikuma, Cecilia M; Gerschenson, Mariana; Chow, Dominic et al. (2008) Mitochondrial oxidative phosphorylation protein levels in peripheral blood mononuclear cells correlate with levels in subcutaneous adipose tissue within samples differing by HIV and lipoatrophy status. AIDS Res Hum Retroviruses 24:1255-62 |
