[41] NEVIRAPINE DID NOT ALTER CELL DIFFERENTIATION, LIPID METABOLISM, INSULIN RESPONSE AND SURVIVAL IN CULTURED ADIPOCYTES

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

25–28 October 2004 - Washington, DC, USA

NEVIRAPINE DID NOT ALTER CELL DIFFERENTIATION, LIPID METABOLISM, INSULIN RESPONSE AND SURVIVAL IN CULTURED ADIPOCYTES

Antiviral Therapy 2004; 9(6):L27 (abstract no. 41)

M Caron¹, M Auclair¹, M Kornprobst¹, C Lagathu¹ and J Capeau^1,2
¹ INSERM U402, Faculty of Medecine Saint-Antoine, Paris, France; and ² Hopital Tenon, Paris, France

OBJECTIVES: Drug-associated adipocyte dysfunction plays a role in the aetiology of adverse symptoms that occur in HIV-infected patients treated with antiretrovirals. Protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and more recently the non-NRTI efavirenz were shown to affect adipocyte functions in vitro. Thus nevirapine (NVP), the other NNRTI used with success in switching studies, was evaluated in vitro for its potential to alter adipocyte functions.

METHODS: 3T3-F442A cells were treated with nevirapine (4.50 μM) all along the differentiation process. Differentiation was estimated at day 7 by the percentage of cells with lipid droplets and the protein expression of adipocyte differentiation markers: SREBP-1, PPAR gamma and C/EBP alpha. Lipid metabolism was evaluated by lipid staining, mRNA expression of fatty acid synthase (FAS) and adipocyte lipid binding protein 2 (aP2), and insulin activation of lipogenesis. Insulin response was evaluated by the insulin-induced tyrosine phosphorylation of the insulin receptor β-subunit and IRS-1, and the activation of ERK 1/2 and Akt/PKB. Apoptosis was estimated by flow cytometry and cytotoxicity by MTT lysis.

RESULTS: In the therapeutic range (4.10 μM), NVP did not alter adipose cell proliferation and differentiation. Indeed the number of cells with lipid droplets (92.95% of total cells), lipid staining, protein expression of SREBP-1, PPAR gamma and C/EBP alpha, and expression of FAS, PPAR gamma and aP2 were unchanged. At higher concentrations (50–100 µM), NVP decreased lipid staining and expression of adipogenic markers. Cell response to insulin was not altered by NVP up to 50 µM: insulin (100 nM) almost normally increased the insulin receptor β-subunit and IRS-1 tyrosine phosphorylation and promoted ERK 1/2 and Akt/PKB activation. Insulin-induced lipogenesis was not affected by NVP up to 10 µM. Up to 50 µM, NVP did not promote cell toxicity and apoptosis (1–3% of cells in sub-G1). At higher concentrations (50–100 µM), NVP induced toxicity and apoptosis.

CONCLUSIONS: Thus, in the therapeutic range (4–10 µM), NVP had no effect on the main adipose cell functions measured in vitro. These data are of interest since NVP-containing regimens are often used as a switching option in patients treated with PI-containing regimens.

Acknowledgements: This work was supported by grants from INSERM and ANRS.

2004-10-25
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