HIV Protease Inhibitors Disrupt Lipid Metabolism by Activating Endoplasmic Reticulum Stress and Inhibiting Autophagy Activity in Adipocytes
Open Access
- 22 March 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (3), e59514
- https://doi.org/10.1371/journal.pone.0059514
Abstract
HIV 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. Cultured 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. Activation 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.This publication has 78 references indexed in Scilit:
- Regulation of lipid droplets by autophagyTrends in Endocrinology & Metabolism, 2011
- Distinct Autophagosomal-Lysosomal Fusion Mechanism Revealed by Thapsigargin-Induced Autophagy ArrestMolecular Cell, 2011
- Pharmacokinetics of plasma lopinavir/ritonavir following the administration of 400/100 mg, 200/150 mg and 200/50 mg twice daily in HIV-negative volunteersJournal of Antimicrobial Chemotherapy, 2010
- Lipodystrophy: pathophysiology and advances in treatmentNature Reviews Endocrinology, 2010
- Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implicationsAmerican Journal of Physiology-Cell Physiology, 2010
- The life of lipid dropletsBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
- Autophagy regulates lipid metabolismNature, 2009
- Is adiposopathy (sick fat) an endocrine disease?International Journal of Clinical Practice, 2008
- Endoplasmic Reticulum Stress in Disease PathogenesisAnnual review of pathology, 2008
- Autophagy Is Activated for Cell Survival after Endoplasmic ReticulumStressMolecular and Cellular Biology, 2006