HIV Protease Inhibitors Disrupt Lipid Metabolism by Activating Endoplasmic Reticulum Stress and Inhibiting Autophagy Activity in Adipocytes
Year: 2013
Type: article
Abstract: BACKGROUND: 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. METHODOLOGY AND PRINCIPAL FINDINGS: 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. CONCLUSION AND SIGNIFICANCE: 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.
Source: PLoS ONE
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: U.S. Department of Veterans Affairs, National Natural Science Foundation of China, National Institutes of Health, National Institute on Deafness and Other Communication Disorders, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Complementary and Integrative Health
Awards: Mechanisms of HIV Protease Inhibitor-Induced Lipid Dysregulation in Adipocytes, 内质网应激在药源性肝损伤中的作用和机制研究, G2622823593, G2771062787, G366399328, VCU Neuroscience Center Core Grant, G4989659415, G5703054046, G6002418859, G668020106, G6829659868, HIV Protease Inhibitors, the Unfolded Protein Response and Atherosclerosis, Prevent HIV protease inhibitor-induced atherosclerosis by Berberine, Nicotinic Acetylcholine Receptor Mediated Bitter Taste Transduction, G8920016036
OpenAlex ID: W2010634632