title: Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress.
abstract: Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein.
authors.affiliation: Department of Medicine, University of Louisville, USA; Alcohol Research Center, University of Louisville, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Mohammad
authors.forename: Diana
authors.initials: D
authors.lastname: Avila
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.forename: Gavin
authors.initials: G
authors.lastname: Arteel
authors.forename: Craig
authors.initials: C
authors.lastname: McClain
authors.forename: Swati
authors.initials: S
authors.lastname: Joshi-Barve
mesh_terms: D000171:Acrolein / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D061945:Caspase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007202:Indicators and Reagents; D000171:Acrolein; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D048670:MAP Kinase Kinase 4; D020169:Caspases