Adipocyte dysfunction is the fundamental basis of widespread metabolic diseases that present clinically as obesity or lipodystrophy. Inflammatory processes contribute significantly to adipocyte dysfunction, leading to dyslipidemia, atherosclerosis and insulin resistance. The mechanisms that incite these processes are unclear. Persistent viral infections are a cause of chronic tissue inflammation. We have investigated mechanisms whereby HIV-1 infection contributes to a complex syndrome of fat atrophy, dyslipidemia and insulin resistance termed """"""""HIV lipodystrophy"""""""". Our studies of the HIV-1 accessory protein Vpr have revealed that: a) Vpr functions as a coactivator of the glucocorticoid receptor (GR) and a corepressor of PPAR3 via a nuclear receptor coregulator binding site in its C-terminal region;b) Vpr blocks preadipocyte differentiation by inhibiting PPAR3;c) a cyclophilin A binding site in the N-terminal region of Vpr contains a non-canonical nuclear receptor coregulator motif that could further enhance GR activity and repress PPAR3;d) mice expressing Vpr in adipose tissue and liver display metabolic defects consistent with increased GR activity and decreased PPAR3 activity in adipocytes;e) Vpr circulates in the blood and can enter adipocytes independent of intact HIV-1. With these findings as a springboard, we propose to specify Vpr-mediated molecular mechanisms of adipocyte dysfunction by achieving the following Specific Aims: 1. Specify the in vivo GR- and PPAR3-dependent mechanisms and gene targets that are responsible for the biochemical and lipid kinetic alterations produced in mice by Vpr;2. Determine the molecular mechanisms whereby Vpr causes cell cycle arrest and blocks differentiation in adipocyte development;3. Determine Vpr's role in promoting cell cycle arrest, blocking differentiation and inducing apoptosis of preadipocytes and adipocytes, when exposed to HIV-infected T lymphocytes;4. Determine in vivo effects of two mechanistically informative mutant forms of Vpr on lipid and energy metabolism: one defective in the LQQLL coregulator binding site, and the other defective in the arginine-rich C-terminus motif associated with Vpr's cell cycle arrest effects in vitro. As a closely collaborative team comprising experts in adipocyte biochemistry, immunology and protein chemistry, we have demonstrated that Vpr transgenic mice recapitulate key lipid kinetic defects we have detailed in humans with HIV infection, and that Vpr can block preadipoctye differentiation in vitro. We are now poised to detail the molecular mechanisms in relevant mouse and adipocyte models utilizing mutant Vpr proteins. Thus, this project is likely to uncover novel pathways of adipocyte dysfunction, lipid dysregulation and insulin resistance resulting from a chronic viral infection.
Inflammation of fat cells leads to common metabolic diseases such as obesity and diabetes Viral infections could be a cause of inflammation in fat cells and patients with chronic HIV infection develop serious fat cell degenerative condition termed """"""""lipodystrophy"""""""" associated with high risk of diabetes and heart disease. The goal of this project is to determine how a protein made by the HIV virus, termed Vpr, can cause chronic inflammation of fat cells and lead to these disorders.
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