title: HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Beth S
authors.initials: BS
authors.lastname: Zha
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Wan
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Weibin
authors.initials: W
authors.lastname: Zha
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.forename: Vijay
authors.initials: V
authors.lastname: Lyall
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D017320:HIV Protease Inhibitors; D051742:Transcription Factor CHOP