The objective of these studies are to measure non-invasively hepatic fatty acid and glucose utilization in human subjects in vivo, to test the hypothesis that normal integration of hepatic metabolic pathways during facing and reseeding is deficient in HIV infected subject with weight loss compared to normal controls and contributes to the wasting diathesis of HIV infection. The hypotheses that such abnormalities are caused by inflammatory monokines and lead d to secondary appetite dysregulation (anorexia) will also be investigated. Three groups will be compared: normal controls, HIV infected subjects with 5-10% weight loss and no history of opportunistic infections, and HIV-infected subjects with >10% weight loss and no history of opportunistic infections. The experimental approach will involve measurement of fluxes through hepatic fatty acid and carbohydrate utilization pathways non- invasiverlyin vivo. This will be done by infusing arable isotopes ((1-d1)) and (U-13C) glucose, (1-d1) - ga;actpse. and 1--13C- palmitate) and measuring isotope enrichments in a number of important metabolites (by isotope ratio or liquid chromatography- mass spectromey), exploiting ceratin newly described """"""""probes"""""""" of intrahepatic metabolism. Metabolic enrichments measured (and physiologic parameters generated) will include: plasma glucose (flux and recycling) plasma palmitate (flux and hepatic re- esterification), urinary glucuronic acid conjugated to acetaminophen (glucose entry into hepatic UDP-glucose by direct and indirect pathways), urinary acetyl-sulfa-methoxazole (enrty of substrates into cytosolic acetyl-CoAS), plasma beta- hydroxybutrae(entry of sustrates into mitochondrial acetyl-CoA), plasma triglycerides (synthesis rate) and expired carbon dioxide (substrate oxidation). The ability to spare glucoeoxidation by increasing gatty acid oxidation during a fast (Rankle cycle) and the prevention of futile cycles during fasting and reseeding (triglyceride hydrolysis/resterification, fatty acted oxidation/ re-synthesis, glycolytic recycling) will be compared in the three groups. Correlations with psalms IL-1, TNF and interferon-alpha concentrations, with urinary nitrogen wasting and body composition, and with the presence of anorexia (evidenced by careful diet history) will be sought. The effect of a reduction in prostacladin E2 levels (with indomethacin or dietary fish oil supplementation) will then be tested. Improved understanding o f metabolic/nutritional abnormalities and inteaviton in HIV infection may lead to therapeutic strategies to combat this extremely common and perhaps critically important complication.
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