title: Ethanol promotes saturated fatty acid-induced hepatoxicity through endoplasmic reticulum (ER) stress response.
abstract: Serum palmitic acid (PA), a type of saturated fatty acid, causes lipid accumulation and induces toxicity in hepatocytes. Ethanol (EtOH) is metabolized by the liver and induces hepatic injury and inflammation. Herein, we analyzed the effects of EtOH on PA-induced lipotoxicity in the liver. Our results indicated that EtOH aggravated PA-induced apoptosis and lipid accumulation in primary rat hepatocytes in dose-dependent manner. EtOH intensified PA-caused endoplasmic reticulum (ER) stress response in vitro and in vivo, and the expressions of CHOP, ATF4, and XBP-1 in nucleus were significantly increased. EtOH also increased PA-caused cleaved caspase-3 in cytoplasm. In wild type and CHOP(-/-) mice treated with EtOH and high fat diet (HFD), EtOH worsened the HFD-induced liver injury and dyslipidemia, while CHOP knockout blocked toxic effects of EtOH and PA. Our study suggested that targeting UPR-signaling pathways is a promising, novel approach to reducing EtOH and saturated fatty acid-induced metabolic complications.
authors.affiliation: Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: hwyi@seu.edu.cn.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yu-Xiang
authors.initials: YX
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Wang
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA.
authors.forename: Cui-Fen
authors.initials: CF
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Medical School, Southeast University, Nanjing 210009, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: xudongwu@nju.edu.cn.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Wu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000139:chemically induced / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism*; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D019308:Palmitic Acid / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019308:Palmitic Acid; D000431:Ethanol; D053148:Caspase 3
keywords: CHOP knockout; ER stress; Ethanol (EtOH); Liver toxicity; Palmitic acid (PA)