title: Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan,             on non-alcoholic steatohepatitis using FLS-ob/ob male mice.
abstract: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a metabolic syndrome characterized by accumulation of hepatic fat, inflammation and varying degrees of fibrosis. Angiotensin (AT)-II has been reported to play a role in the establishment of NASH. This study examined the effects of an AT-II receptor blocker, irbesartan, on NASH using fatty liver Shionogi (FLS)-ob/ob male mice as the closest animal model of human metabolic syndrome-related NASH. Irbesartan (30 mg/kg/day) was orally administered to FLS-ob/ob mice for 12 weeks (irbesartan group). The effects of irbesartan on steatohepatitis were examined using factors including steatosis, fibrosis, inflammation and oxidative stress. The areas of hepatic fibrosis and hepatic hydroxyproline content were significantly lower in the irbesartan group compared to controls. The areas of α-smooth muscle actin-positivity and F4/80-positive cells were significantly decreased in the irbesartan group. The percentage of 8-hydroxy-2-deoxyguanosine (8-OHdG)-positive cells and 8-OHdG DNA content were significantly decreased in the irbesartan group compared to controls. Levels of RNA expression for procollagen I, transforming growth factor β1, tumor necrosis factor-α, sterol regulatory element-binding protein 1c and fatty acid synthase were significantly lower in the irbesartan group compared to controls. In contrast, the gene expression of peroxisome proliferator activated receptor-α was significantly higher in the irbesartan group compared to controls. Irbesartan administration improved hepatic steatosis and attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Kupffer cells and reducing oxidative stress.
authors.affiliation: Division of Medicine and Clinical Science, Department of Multidisciplinary                     Internal Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504,                     Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kato
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koda
authors.forename: Manabu
authors.initials: M
authors.lastname: Kishina
authors.forename: Shiho
authors.initials: S
authors.lastname: Tokunaga
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Matono
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sugihara
authors.forename: Masaru
authors.initials: M
authors.lastname: Ueki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000199:Actins / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D000077405:Irbesartan; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D024042:Collagen Type I; D047493:PPAR alpha; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D064429:Fatty Acid Synthases; D003849:Deoxyguanosine; D000077405:Irbesartan