title: Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress.
abstract: Aldehyde reductase (Akr1a) has been reported to be involved in the biosynthesis of ascorbic acid (AsA) in the mouse liver. Because Akr1a is expressed at high levels in the liver, we aimed to investigate the role of Akr1a in liver homeostasis by employing a carbon tetrachloride (CCl4)-induced hepatotoxicity model. Akr1a-deficient (Akr1a(-/-)) and wild-type (WT) mice were injected intraperitoneally with CCl4 and the extent of hepatic injury in the acute phase was assessed. Liver damage was heavier in the Akr1a(-/-) mice than in the WT mice. Furthermore, severe hepatic steatosis was observed in the livers of Akr1a(-/-) mice compared to WT mice and was restored to the levels in WT mice by AsA supplementation. Since the presence or absence of AsA had no effect on the decrease in CYP2E1 activity after the CCl4 treatment, it appears that AsA plays a role in the process after the bioactivation of CCl4. Biomarkers for oxidative stress and ER stress were markedly increased in the livers of Akr1a(-/-) mice and were effectively suppressed by AsA supplementation. Based on these collective results, we conclude that Akr1a exerts a protective effect against CCl4-induced hepatic steatosis by replenishing AsA via its antioxidative properties.
authors: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
authors: Ryusuke
authors: R
authors: Akihara
authors: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
authors: Takujiro
authors: T
authors: Homma
authors: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan.
authors: Jaeyong
authors: J
authors: Lee
authors: Department of Bio-functional Science, Faculty of Pharmacological Science, Kyushu University, Fukuoka 812-8582, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors: Ken-Ichi
authors: K
authors: Yamada
authors: Department of Internal Medicine, Osaka Hospital, Japan Community Healthcare Organization, Osaka 553-0003, Japan.
authors: Satoshi
authors: S
authors: Miyata
authors: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata 990-9585, Japan. Electronic address: jfujii@med.id.yamagata-u.ac.jp.
authors: Junichi
authors: J
authors: Fujii
mesh_terms: D000449:Aldehyde Reductase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D015870:Gene Expression; D005978:Glutathione / Q000819:agonists / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D002251:Carbon Tetrachloride; D000449:Aldehyde Reductase; D054464:Peroxiredoxins; D019392:Cytochrome P-450 CYP2E1; C000617651:cytochrome P-450 2E1, mouse; D005978:Glutathione; D001205:Ascorbic Acid
keywords: Ascorbic acid; Carbon tetrachloride; ER stress; Oxidative stress; Steatosis