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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040995-02
Application #
3241537
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1989-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hudgins, Lisa C; Baday, Aline; Hellerstein, Marc K et al. (2008) The effect of dietary carbohydrate on genes for fatty acid synthase and inflammatory cytokines in adipose tissues from lean and obese subjects. J Nutr Biochem 19:237-45
Hellerstein, M K (2001) Pathophysiology of body composition and metabolic abnormalities in HIV-infection: therapeutic implications. Int J Sport Nutr Exerc Metab 11 Suppl:S105-10
Strawford, A; Barbieri, T; Van Loan, M et al. (1999) Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA 281:1282-90
Hoh, R; Pelfini, A; Neese, R A et al. (1998) De novo lipogenesis predicts short-term body-composition response by bioelectrical impedance analysis to oral nutritional supplements in HIV-associated wasting. Am J Clin Nutr 68:154-63
Macallan, D C; Fullerton, C A; Neese, R A et al. (1998) Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans. Proc Natl Acad Sci U S A 95:708-13
Hellerstein, M K; Neese, R A; Linfoot, P et al. (1997) Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study. J Clin Invest 100:1305-19
Hellerstein, M K; Letscher, A; Schwarz, J M et al. (1997) Measurement of hepatic Ra UDP-glucose in vivo in rats: relation to glycogen deposition and labeling patterns. Am J Physiol 272:E155-62
Hellerstein, M K; Schwarz, J M; Neese, R A (1996) Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr 16:523-57
Hellerstein, M K; Wu, K; McGrath, M et al. (1996) Effects of dietary n-3 fatty acid supplementation in men with weight loss associated with the acquired immune deficiency syndrome: Relation to indices of cytokine production. J Acquir Immune Defic Syndr Hum Retrovirol 11:258-70
Hellerstein, M K (1996) Synthesis of fat in response to alterations in diet: insights from new stable isotope methodologies. Lipids 31 Suppl:S117-25

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