title: Binge alcohol consumption aggravates oxidative stress and promotes pathogenesis of NASH from obesity-induced simple steatosis.
abstract: The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the "first hit" and an unknown "second hit." We hypothesized that "a binge" could be a "second hit" to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that "a binge" serves as a "second hit" for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Minato
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Tsutsumi
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Tsuchishima
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hayashi
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsue
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Toshikuni
authors.affiliation: Department of Gastroenterology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Tomiyasu
authors.initials: T
authors.lastname: Arisawa
authors.affiliation: Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
authors.forename: Joseph
authors.initials: J
authors.lastname: George
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D063425:Binge Drinking / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D020334:Rats, Inbred OLETF; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000447:Aldehydes; D014409:Tumor Necrosis Factor-alpha; D019392:Cytochrome P-450 CYP2E1; C027576:4-hydroxy-2-nonenal