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Journal of Lipid Research, Vol. 44, 103-108, January 2003
Copyright © 2003 by Lipid Research, Inc.

The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

Catarina Cammalleri^*, and Ralph J. Germinario^1,*,,,**

^* Lady Davis Institute, SMBD-Jewish General Hospital, Quebec, Canada
Concordia University, Department of Biology, Quebec, Canada
McGill University, Department of Medicine, Quebec, Canada
^** McGill AIDS Center, Montreal, Quebec, Canada

¹ To whom correspondence should be addressed. e-mail: ralph.germinario{at}mcgill.ca

The objective of our research was to investigate the effects of the protease inhibitors ritonavir, saquinavir, and indinavir on triglyceride synthesis, lipolysis, insulin binding, and signaling in differentiating 3T3 L1 pre-adipocytes. Saquinavir, ritonavir, and indinavir all stimulated triglyceride (TG) synthesis. Additionally, all concentrations of protease inhibitors employed (i.e., 0.1 µM to 10 µM) significantly decreased insulin-stimulated TG synthesis. No effects of any of the protease inhibitors were observed either on basal lipolysis or after stimulation of lipolysis with 100 nM noradrenaline. Specific ¹²⁵I-insulin binding was observed to be decreased by exposure to all the protease inhibitors throughout the period of adipocyte phenotype development. This was mediated by indinavir through a receptor decrease and had no effect on receptor affinity. During differentiation with ritonavir (i.e., 1–11 days post addition of differentiating cocktail), insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation was ascertained (day 11) and found to be decreased in the ritonavir exposed cells when compared with control cells. The results reported herein demonstrate protease inhibitor effects on basal TG synthesis while exhibiting decreased insulin-stimulated TG synthesis at physiological concentrations of protease inhibitors.

These effects may be subsequent to decreased insulin binding and/or IRS-1 tyrosine phosphorylation.

Abbreviations: HAART, highly active antiretroviral therapy; IRS-1, insulin receptor substrate-1; PI, protease inhibitors; TG, triglyceride

Supplementary key words triglyceride synthesis • lipolysis • insulin lipogenic response • binding and signaling

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