title: Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes.
abstract: A portion of human immunodeficiency virus (HIV)-infected patients undergoing protease inhibitor (PI) therapy concomitantly consume or abuse alcohol leading to hepatic injury. The underling mechanisms are not known. We hypothesize that HIV PIs aggravate alcohol-induced liver injury through an endoplasmic reticulum (ER) stress mechanism. To address this, we treated mice, primary mouse hepatocytes (PMHs), and primary human hepatocytes (PHHs) with alcohol and the HIV PIs ritonavir (RIT) and lopinavir (LOP). In mice, RIT and LOP induced mild ER stress and inhibition of sarco/ER calcium-ATPase (SERCA) without significant increase in serum alanine aminotransferase (ALT) levels. However, a single dose of alcohol plus the two HIV PIs caused a more than five-fold increase in serum ALT, a synergistic increase in alcohol-induced liver lipid accumulation and ER stress response, and a decrease of SERCA. Mice treated with chronic HIV PIs and alcohol developed moderate liver fibrosis. In PMHs, the HIV drugs plus alcohol also inhibited SERCA expression and increased expression of glucose-regulated protein 78, C/EBP homologous protein, sterol regulatory element-binding protein 1c, and phosphorylated c-Jun N-terminal kinase 2, which were accompanied by a synergistic increase in cell death compared with alcohol or the HIV drugs alone. In PHHs, treatment with RIT and LOP or alcohol alone increased messenger RNA of spliced X box-binding protein 1 and decreased SERCA, which were accompanied by reduced levels of intracellular calcium. Alcohol combined with the HIV drugs significantly reduced intracellular calcium levels and potentiated cell death, which was comparable to the cell death caused by the SERCA inhibitor thapsigargin.
  
  
  CONCLUSIONS
  Our findings suggest the possibility that HIV PIs potentiate alcohol-induced ER stress and injury through modulation of SERCA and maintaining calcium homeostasis could be a therapeutic aim for better care of HIV patients.
authors.affiliation: Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Eddy
authors.initials: E
authors.lastname: Kao
authors.forename: Masao
authors.initials: M
authors.lastname: Shinohara
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.forename: Mo Yin
authors.initials: MY
authors.lastname: Lau
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000633:toxicity; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000473:pathology*; D061466:Lopinavir / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D019438:Ritonavir / Q000633:toxicity; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C506944:Atp2a1 protein, mouse; D002492:Central Nervous System Depressants; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D061466:Lopinavir; D000431:Ethanol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019438:Ritonavir; D002118:Calcium