[42] PIS AND NRTIS WITH ADVERSE EFFECTS ON ADIPOCYTE LIPID METABOLISM AND SURVIVAL ALTER THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES AND ADIPONECTIN IN ADIPOCYTES

6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

25–28 October 2004 - Washington, DC, USA

PIs AND NRTIs WITH ADVERSE EFFECTS ON ADIPOCYTE LIPID METABOLISM AND SURVIVAL ALTER THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES AND ADIPONECTIN IN ADIPOCYTES

Antiviral Therapy 2004; 9(6):L27 (abstract no. 42)

C Lagathu¹, JP Bastard^1,2, M Auclair¹, M Maachi^1,2, M Kornprobst¹, J Capeau^1,2 and M Caron¹
¹ INSERM U.402 and IFR65 Saint-Antoine Faculty of Medicine, University Pierre and Marie Curie, Paris, France; and ² Biochemistry Department Tenon Hospital, Paris, France

OBJECTIVES: The lipodystrophic syndrome is a major adverse effect of highly active antiretroviral therapy (HAART), associated with altered circulating levels and adipose tissue mRNA expression of pro-inflammatory cytokines (IL-6 and TNF-α) and adiponectin. Proinflammatory cytokines and adiponectin, which are secreted by adipose tissue, regulate fat metabolism, insulin sensitivity and adipose cell apoptosis. We examined the direct effects of individual antiretrovirals on lipid metabolism and cytokine and adiponectin production by cultured adipocytes

METHODS: Differentiating 3T3-F442A cells and differentiated 3T3-L1 adipocytes were treated for 12 or 4 days, respectively, with protease inhibitors (PIs) indinavir, nelfinavir, amprenavir, lopinavir and ritonavir, or nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine, at near-C_max concentrations. Lipid metabolism was estimated by Oil Red O staining of intracellular lipids, mRNA expression of fatty acid synthase and adipocyte lipid binding protein 2, and insulin activation of lipogenesis. Apoptosis was estimated by flow cytometry. The expression and secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1-β) and adiponectin was evaluated by real-time RT-PCR and ELISA.

RESULTS: Chronic treatment of 3T3-F442A differentiating adipocytes and differentiated 3T3-L1 adipocytes with PIs and NRTIs reduced lipid accumulation, mRNA expression of lipid markers and insulin-induced lipogenesis. IL- 6, TNF-α, IL-1-β and adiponectin expression and secretion were markedly altered in differentiating 3T3- F442A adipocytes. PIs had either no effect on differentiated 3T3-L1 adipocytes (TNF-α expression and secretion) or their effalphaect was less marked than in 3T3- F442A cells. Indinavir and amprenavir did not alter cytokine or adiponectin secretion and expression by mature adipocytes. The effects of stavudine and zidovudine on differentiating and mature adipocytes were similar, despite the difference of treatment procedure. The drugs with the strongest effect on TNF-α expression also increased adipocyte apoptosis, contrary to the drugs that only moderately increased TNF-α expression.

CONCLUSIONS: These results suggest that increased cytokine and decreased adiponectin secretion and expression induced by some PIs and NRTIs may contribute to the adipose tissue loss (via apoptosis and lipid leakage) and the insulin resistance associated with the lipodystrophy syndrome.

2004-10-25
42

Copyright © 2004 - 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.