10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

EFAVIRENZ INDUCES ALTERATIONS IN LIPID METABOLISM THROUGH AMPK ACTIVATION

Antiviral Therapy 2008; 13(Suppl. 4):A24 (abstract no. P-03)

A Blas-García, D Ballesteros, D Monleón, JM Morales, M Rocha, VM Víctor, N Apostolova and JV Esplugues
Department of Pharmacology and Department of Molecular Image, Faculty of Medicine, University of Valencia and CIBEREHD, Valencia, Spain

Recent evidence suggests that the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) contributes to changes in lipid and body fat composition that are implicated in lipoatrophy. As the liver is an important organ in lipid metabolism, we have evaluated the effects of clinically used concentrations of EFV on mitochondrial function and cellular lipid metabolism in vitro and the implication of AMP-activated protein kinase (AMPK), the master switch for regulation of cellular bioenergetics, in these processes. Oxygen consumption in non-HIV-infected Hep3B cells was measured with a Clark-type electrode. Following incubation (1 h) with EFV (10, 25 or 50 µM), intracellular ATP was measured by fluorescence, mitochondrial membrane potential (ΔΨ_m), which is indicative of mitochondrial function, was analysed by static cytometry and AMPK was evaluated by western blotting. In order to further study the implication of this enzyme, selected experiments were performed in cells pretreated (30 min) with the AMPK inhibitor compound C (20 µM). The expression of the fatty acid transporter CD36 was analysed using PCR and the intracellular lipid content was determined by nuclear magnetic resonance after 4 h of incubation with EFV. EFV produced an immediate reduction of mitochondrial function, evident by the significant and dose-dependent inhibition of mitochondrial oxygen consumption and the decrease of intracellular ATP and ΔΨ_m. This metabolic stress promoted the activation of AMPK, triggering several of its signalling pathways, as EFV induced an increment in CD36 messenger RNA expression and in intracellular lipid content that could have been a result of the formation of lipid droplets. This intracellular lipid increase was not present in cells treated with compound C, which points to a key role for AMPK in these mechanisms. Given that EFV treatment is usually prolonged, these mechanisms might affect the general regulation of lipid metabolism and could cause the alterations that are characteristic of lipoathrophy.

Download PDF of this abstract.

2008-11-06
P-03

Copyright © 2008 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.