7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

EFFECT OF ATAZANAVIR AND RITONAVIR ON THE DIFFERENTIATION AND ADIPOKINE SECRETION OF HUMAN SUBCUTANEOUS AND OMENTAL PREADIPOCYTES

SP Jones, C Waitt, DJ Back and M Pirmohamed^1
1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK

Antiviral Therapy 2005; Supplement 3:L21 (abstract no. 29)

BACKGROUND: Treatment of HIV with some protease inhibitors (PIs) has been associated with dyslipidaemia, insulin resistance and fat redistribution. The mechanisms of fat redistribution are not well understood, although it has been hypothesized that PIs may alter the differentiation of subcutaneous and visceral adipocytes in a disparate manner. Whilst ritonavir (RTV), appears to inhibit the differentiation of subcutaneous adipocytes and alters adipokine expression, the effects of atazanavir (ATV) remain unknown. The aim of this study was to investigate whether isolated human preadipocytes display a region-specific sensitivity to the effects of RTV and ATV by examining differentiation, as well as adipokine secretion following 10 days of exposure.

METHODS: Paired subcutaneous (Sc) and omental (Om) human preadipocytes (n=8) were induced to differentiate for 6 days, before being exposed to ATV or RTV (1–20 µM) for 10 days. Lipid metabolism was assessed by Oil Red O staining and GPDH enzyme activity, whilst expression of leptin and adiponectin secretion were assessed by ELISA.

RESULTS: There were no significant differences in adipocyte differentiation between Sc and Om adipocytes, although repeated exposure to RTV, but not ATV, at physiological concentrations led to significant reductions in both triglyceride accumulation (~26%) and GPDH activity (~45%) vs vehicle control respectively. Adiponectin and leptin secretion was higher in drug-naïve Sc than in Om adipocytes (7599 ±443 vs 6253 ±120 pg/ml, P<0.01; 226 ±15 vs 137 ±7, P<0.001 respectively). There were no differences in adiponectin secretion for any of the ATV treatments in both Sc and Om adipocytes, whilst significant reductions were evident at 10 and 20 µM for RTVexposed adipocytes from both depots, although a greater reduction was evident for the Sc treatments. In contrast, both ATV and RTV altered leptin secretion with 10 µM increasing secretion by 73 and 40% respectively within Sc adipocytes, whilst 20 µM led to significant reductions (–30, –40% respectively).

CONCLUSIONS: In conclusion, our data indicate that RTV, but not ATV, can inhibit differentiation of Sc and Om adipocytes to a similar extent. Region-specific differences, however, were apparent for adiponectin and leptin secretion. The role of region-specific alterations in adipokine secretion and apoptosis in the pathogenesis of HIV-lipodystrophy requires further attention.

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2005-11-13
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