title: Carnosic acid attenuates acute ethanol-induced liver injury via a SIRT1/p66Shc-mediated mitochondrial pathway.
abstract: Ethanol-induced liver injury is associated with oxidative stress and hepatocyte apoptosis. We previously demonstrated that SIRT1/p66Shc pathway activation attenuates hepatocyte apoptosis in liver ischemia/reperfusion. The current study aimed to investigate whether carnosic acid (CA), a natural antioxidant, can inhibit acute ethanol-induced apoptosis of hepatocytes and to determine the effect of SIRT1/p66Shc on this process. Our results showed that CA pretreatment significantly reduced ethanol-induced histologic damage, serum aminotransferase activity, and oxidative stress in rats. Importantly, CA pretreatment increased SIRT1 expression following ethanol exposure. Furthermore, p66Shc expression was negatively correlated with SIRT1 expression. Consistent with the results demonstrating p66Shc inhibition, CA pretreatment inhibited the release of cytochrome C and apoptosis-inducing factor (AIF) from mitochondria. After exposing L02 cells to ethanol, the increased SIRT1 expression induced by CA was abrogated by pharmacologic SIRT1 inhibition or the use of siRNA against SIRT1. Additionally, SIRT1 inhibition significantly abrogated the suppression of p66Shc expression and mitochondrial translocation induced by CA. Accordingly, CA-induced decreases in the release of cytochrome C and AIF and in mitochondrial apoptosis were nearly abolished by SIRT1 knockdown. These data indicated that CA-activated SIRT1 is protective against ethanol treatment. In summary, CA attenuates acute ethanol-induced liver injury via a SIRT1/p66Shc-mediated mitochondrial pathway.
authors: a Xiangya Hospital, Central South University, Changsha 410008, P.R. China.
authors: Xinyao
authors: X
authors: Tian
authors: b Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian 116027, P.R. China.
authors: Yan
authors: Y
authors: Hu
authors: c Department of Pharmacology, Dalian Medical University, Dalian 116044, P.R. China.
authors: Mingzhu
authors: M
authors: Li
authors: a Xiangya Hospital, Central South University, Changsha 410008, P.R. China.
authors: Kun
authors: K
authors: Xia
authors: d Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.|e Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P.R. China.
authors: Jiye
authors: J
authors: Yin
authors: d Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.|e Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P.R. China.
authors: Juan
authors: J
authors: Chen
authors: d Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China.|e Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P.R. China.
authors: Zhaoqian
authors: Z
authors: Liu
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000378:metabolism*
chemical_list: D045784:Abietanes; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D034741:RNA, Small Interfering; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000431:Ethanol; D045304:Cytochromes c; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C018381:salvin
keywords: AIF; SIRT1; acide carnosique; carnosic acid; cytochrome C; ethanol; mitochondrial; p66Shc; éthanol