HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.

Beth S Zha,Vijay Lyall,Martin Wabitsch,Guangji Wang,Xiaoshan Wan,Phillip B Hylemon,Jun Zhou,Xiaoxuan Zhang,Huiping Zhou,Weibin Zha

doi:10.1371/journal.pone.0059514

Abstract

BackgroundHIV protease inhibitors (PI) are core components of Highly Active Antiretroviral Therapy (HAART), the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER) stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Methodology and Principal FindingsCultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP−/− mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Conclusion and SignificanceActivation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.

Highlights

The development of HIV protease inhibitors (PIs) was one of the most significant advances of the past two decades for controlling HIV infection
Activation of endoplasmic reticulum (ER) stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes
Our previous studies indicate that activation of ER stress plays a critical role in HIV PI-induced dysregulation of lipid metabolism in macrophages and hepatocytes [3,40]

Summary

Introduction

The development of HIV protease inhibitors (PIs) was one of the most significant advances of the past two decades for controlling HIV infection. HAART has been linked to cardiovascular complications and metabolic syndrome in HIV-1 patients It has been well-documented that HIV PIs induce many of these deleterious effects including early induction of insulin resistance, dysregulation of lipid metabolism, and inflammation, all of which are cornerstones of cardiovascular and metabolic diseases [1,2]. An extensive effort has been put forth to study the mechanism underlying HIV PI-induced side effects Both in vitro and in vivo animal studies from our laboratory and others’ have linked the activation of endoplasmic reticulum (ER) stress to HIV PI-induced cell apoptosis, dyslipidemia, inflammation, and insulin resistance in several metabolically important cell types including hepatocytes, macrophages, and adipocytes [3,4,5,6,7]. Little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome

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