HIV protease inhibitors activate the ER stress response and disrupt the lipid metabolism in 3T3‐L1 adipocytes

Abstract

HIV protease inhibitor‐induced lipodystrophic syndrome is a major side effect of current anti‐HIV therapy. However, the underlying molecular mechanism remains unclear. We have recently shown that HIV PI‐induced ER stress and activation of the unfolded protein response (UPR) represents an important cellular mechanism by which HIV PIs disrupt lipid metabolism and induce inflammation in hepatocytes and macrophages. The aim of this study was to determine if HIV PIs also induce ER stress, activate the UPR, and affect the lipid metabolism and differentiation in adipocytes.MethodsMouse 3T3‐L1 adipocytes were used in this study. The effect of individual HIV PI on differentiation and lipid accumulation was examined by Oil red O staining. Activation of the UPR was determined by real time RT‐PCR and Western Blot analysis. The expression of adipokines/cytokines was determined by real‐time PCR and ELISA.ResultsDifferent HIV PIs had different effects on the UPR activation, cell differentiation, and lipid metabolism in adipocytes. Both lopinavir and ritonavir dose‐dependently activated the UPR, increased IL‐6 expression, reduced adiponectin expression, and induced cell apoptosis. But amprenavir had less effect.ConclusionsHIV PI‐induced ER stress response and activation of the UPR may represent a critical molecular mechanism underlying HIV PI‐associated lipodystrophy and metabolic syndrome.