title: PI3K/Akt pathway activation was involved in acute ethanol-induced fatty liver in mice.
abstract: Accumulating evidences support the important roles of sterol regulatory element-binding protein-1 (SREBP-1) activation in ethanol-induced fatty liver, but the underlying mechanisms for its activation are not fully understood. Recent studies have demonstrated that phosphatidylinositol 3 kinase (PI3K)/Akt pathway activation could enhance SREBP-1 activity. The current study was designed to investigate the potential roles of PI3K/Akt pathway in acute ethanol-induced fatty liver in mice. In the first experiment, mice were treated with ethanol (2.5 or 5 g/kg bw) or isocaloric/isovolumetric maltose-dextrin solution, and sacrificed at several time points after ethanol exposure. As expected, ethanol dose-dependently increased the hepatic triglyceride (TG) levels and the protein levels of the mature form of SREBP-1 (n-SREBP-1). The phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β) was significantly increased in mice treated with ethanol (5 g/kg bw), while the protein levels of PI3K-p85 were significantly reduced. To confirm the roles of PI3K/Akt pathway, mice were then pretreated with wortmannin (0.7 or 1.4 mg/kg bw), a specific PI3K/Akt pathway inhibitor, before exposure to ethanol. Interestingly, a dual effect of wortmannin was observed. Low dose of wortmannin significantly reduced the hepatic TG levels, while high dose of wortmannin aggravated ethanol-induced fatty liver. The ratio of LC3II/LC3I of wortmannin (1.4 mg/kg bw) group mice was significantly increased, while the p62 protein level was significantly decreased compared to those of ethanol group, which indicated that wortmannin (1.4 mg/kg bw) might suppress the lipid degradation by autophagy. These results supported the hypothesis that PI3K/Akt activation might be involved in acute ethanol-induced fatty liver, and PI3K/Akt inhibitors might have therapeutic potential for the treatment of ethanol-induced fatty liver.
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Shandong Province, Jinan City 250012, People's Republic of China. zengtao1311@yahoo.com.cn
authors.forename: Tao
authors.initials: T
authors.lastname: Zeng
authors.forename: Cui-Li
authors.initials: CL
authors.lastname: Zhang
authors.forename: Fu-Yong
authors.initials: FY
authors.lastname: Song
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Zhao
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Yu
authors.forename: Zhen-Ping
authors.initials: ZP
authors.lastname: Zhu
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Xie
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D047428:Protein Kinase Inhibitors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000077191:Wortmannin