Characterization of HIV protease inhibitors using large scale metabolomics of an adipocyte cell model in vitro
Flint, O., Elosua, C., Parker, R., Hamilton, C., & Noor, M. (2005, July). Characterization of HIV protease inhibitors using large scale metabolomics of an adipocyte cell model in vitro. Presented at 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, July 24 - 27, .
INTRODUCTION: Treatment of HIV with some protease inhibitors (PI) is associated with dyslipidemia, insulin resistance and fat redistribution. At the cellular level, lipid synthesis and storage, glucose uptake and storage and insulin signaling are among several known targets of PI in adipocytes. We have comprehensively investigated the effect of PIs on the cellular metabolic state of cultured adipocytes using metabolomics, an emerging technology that allows simultaneous measurement of nearly all intracellular metabolites.
METHODS: We exposed 3T3-L1 adipocytes for 16 hours to lopinavir (LPV), indinavir (IDV), ritonavir (RTV), and atazanavir (ATV) at 30 ?M and nelfinavir (NFV) at 10 ?M. All known cellular metabolites were analyzed by gas or liquid chromatography mass spectrometry. The expression of each endogenous metabolite was analyzed using pattern recognition tools using a statistical process control method (Spotfire). Treatment comparisons were by ANOVA using Dunnett's correction.
RESULTS: Of a total of 146 metabolites identified and characterized, the intracellular concentrations of 25 (17%) were significantly reduced by one or more of the PI tested (p RTV (14) > IDV (13) > NFV (11) >> ATV (2).
CONCLUSIONS: The pattern of metabolite reductions induced by some PI's is indicative of glucose deprivation with a shift towards gluconeogenesis and glycolysis over oxidative metabolism. Our data provide additional evidence for a direct relationship between inhibition of glucose uptake and subsequent reductions in intermediate metabolites of lipid synthesis, a mechanism by which some PIs may directly contribute to lipoatrophy.