title: Deletion of circadian gene Per1 alleviates acute ethanol-induced hepatotoxicity in mice.
abstract: The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1-/- mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1-/- mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARγ) and its target genes related to TG synthesis are remarkably down-regulated in Per1-/- mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARγ and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing 210094, China. Electronic address: wavetaowang@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Yibei
authors.initials: Y
authors.lastname: Zhan
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D017353:Gene Deletion; D056945:Hep G2 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D000431:Ethanol
keywords: ACC1; ACO; ALD; CAT; CD36; CPT1; CYP2E1; Circadian; DGAT; Ethanol; FAS; GSH; HO-1; Hepatic lipogenesis; Liver injury; MDA; PPAR; Per1; Period; SCD1; SOD; SREBP-1c; TG; WT; ZT; aP2; acetyl-CoA carboxylase 1; acyl-CoA oxidase; acyl-CoA:diacylglycerol acyltransferase; alcohol liver disease; carnitine palmitoyltransferase 1; catalase; cytochrome P450-2E1; fatty acid binding protein 4; fatty-acid synthase; fatty-acid translocase; glutathione; heme oxygenase-1; malondialdehyde; peroxisome proliferators activated receptor; stearoyl-CoA desaturase 1; sterol regulatory element binding protein-1c; superoxide dismutase; triglyceride; wild-type; zeitgeber time