6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 25–28 October 2004 - Washington, DC, USA

EFFECTS OF HAART ON RESISTIN AND PERILIPIN mRNA EXPRESSION IN MOUSE 3T3-L1 AND PRIMARY HUMAN ADIPOCYTES

Antiviral Therapy 2004; 9(6):L28 (abstract no. 44)

PV Nerurkar¹, L Pearson¹, JK Cope¹, K Adeli², J Frank¹ and VR Nerurkar^1
1University of Hawaii at Manoa, Honolulu, HI, USA; and ²Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada

Efficacy of HAART is complicated due to various side effects including decrease in subcutaneous fat (lipoatrophy), increased visceral fat and insulin resistance. Mechanistic studies implicate decrease in adipose transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and mitochondrial toxicity-associated apoptosis to be involved in lipoatrophy, while increased visceral fat could arise from increased adipogenesis. PPARγ is involved in regulating the expression of adipocytokine, resistin and lipid droplet specific protein, perilipin, implicated in adipocyte differentiation and obesity-associated insulin resistance. The aim of our study was to test the combined effects of protease inhibitors (PIs) such as ritonavir (RTV), lopinavir (LPV/r) and nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as combivir (CBV, containing zidovudine + lamivudine) on the release of caspase-3 as a measure of apoptosis, production of reactive oxygen species (ROS) and mRNA expression of PPARγ-regulated genes, perilipin and resistin in 3T3-L1 mouse and primary human subcutaneous pre-adipocytes. Our data indicate that RTV, LPV and CBV, either singly or in combination, significantly increase adipocyte differentiation in mouse and primary human pre-adipocytes, as measured by Oil Red staining and cellular triglycerides levels (P<0.05), with a concomitant increase in both resistin and perilipin mRNA expression (P<0.05). Treatment with PI and/or NRTI had no effect on either ROS production or apoptosis in both cell types. Current strategies to manage HAART-associated metabolic complications include PPARγ agonists such as rosiglitazone that increase insulin sensitivity and ameliorate lipoatrophy by increasing adipocyte differentiation. Based on our in vitro data, it would therefore appear that PPARγ agonists may not be suitable for treating HIV-infected patients on HAART regimens that specifically increase adipocyte differentiation. Understanding the underlying pathophysiological mechanisms can assist in identifying new therapeutic molecular targets to treat HAART-associated metabolic disorders and/or newer drug design.

Supported by: NCRR, NIH (G12RR003061 and P20RR011091) and the Hawaii Community Foundation (20012061) grants.

2004-10-25
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