title: Inhibition of aldose reductase ameliorates diet-induced nonalcoholic steatohepatitis in mice via modulating the phosphorylation of hepatic peroxisome proliferator-activated receptor α.
abstract: Aldose reductase (AR) is involved in the pathogenesis of nonalcoholic steatohepatitis. This study aimed to determine the mechanism by which AR affects the development of murine diet-induced nonalcoholic steatohepatitis. Steatohepatitis was induced in C57BL/6 mice by administration of a methionine-choline-deficient (MCD) diet, a commonly used nutrition-induced model of steatohepatitis. Hematoxylin and eosin staining was used for histological analyses. Western blot analyses were used to determine protein expression levels and quantitative polymerase chain reaction was used to analyze mRNA expression levels. The results showed that the AR protein expression level was significantly higher in C57BL/6 mice fed the MCD diet than in mice fed the control diet. Diet-induced hepatic steatosis and necroinflammation were attenuated in the MCD diet-fed mice treated with the AR inhibitor, zopolrestat. The ameliorating effect of AR inhibition on steatohepatitis was associated with decreased levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced expression of phosphorylated peroxisome proliferator-activated receptor (PPAR)α and increased mRNA expression of acyl coenzyme A oxidase. These data indicated that induction of hepatic AR expression in mice with steatohepatitis resulted in the phosphorylation of PPARα and suppression of PPARα activity. Inhibition of AR decreased lipid accumulation and inflammation in the liver, at least in part through the modulation of PPARα phosphorylation and PPARα transcriptional activity.
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Duanyu
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Yanxue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Mengguang
authors.initials: M
authors.lastname: Qiu
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biology, School of Life Sciences, Longyan University, Longyan, Fujian 364000, P.R. China.
authors.forename: Longxin
authors.initials: L
authors.lastname: Qiu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D047492:Peroxisome Proliferator-Activated Receptors; D010793:Phthalazines; C067172:zopolrestat; D000449:Aldehyde Reductase