In addition to the presence of opportunistic infections and malignancies, AIDS is characterized by a syndrome of relentless wasting that cannot be explained solely on the basis of poor food intake and malabsorption. The wasting in AIDS is so striking that the name for AIDS in Africa is """"""""slim"""""""". Infection is often accompanied by marked disturbances in intermediary metabolism, in particular, hypertriglyceridemia. Work from many laboratories including our own indicate that cytokines, the peptide hormones that coordinate the immune response, are responsible for the hyperlipidemia. Cytokines are also thought to mediate the wasting of infection. We have found a high prevalence of hypertriglyceridemia in AIDS patients and propose to study the link between this disturbance in lipid metabolism and wasting. We hypothesize that hypertriglyceridemia in AIDS is secondary to increased circulating levels of cytokines and precedes the onset of wasting. The initial defect in lipid metabolism is increased production of VLDL, while the onset of cachexia correlates with decreased storage of triglyceride, mediated by decreases in lipoprotein lipase or increased futile cycling of fatty acid and triglyceride. This transition is brought about either by increasing levels of cytokines or by synergistic effects of more than one cytokine. To test these hypotheses: We will characterize the hyperlipidemia in AIDS by determining the lipoprotein and apoproteins that are increased. We will define the mechanisms of hypertriglyceridemia by measuring the levels of lipoprotein lipase (whose inhibition has been linked to the syndrome of cachexia in model infections) and measuring lipid clearance in AIDS patients. We will measure the levels of cytokines in the circulation of AIDS patients. We will characterize the wasting in AIDS patients by measuring lean body mass and percent fat using bioelectrical impedance and determining metabolic rates using indirect calorimetry. We will quantify futile cycling by measuring glycerol and fatty acid turnover as well as fat oxidation. We will correlate disturbances in lipid metabolism and levels of cytokines with wasting in AIDS patients. Finally, we will develop animal models of cytokine induced wasting by studying the effects of the cytokines that are elevated in AIDS patients on wasting and lipid metabolism in mice.
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