title: Chronic vitamin C insufficiency aggravated thioacetamide-induced liver fibrosis in gulo-knockout mice.
abstract: Given the involvement of oxidative stress in liver-disease- or hepato-toxicant-induced hepatic damage and fibrosis, antioxidants are an effective preventive and therapeutic tool. The beneficial results of vitamin C, one of the physiological antioxidants, have been observed both in experimental animals and in humans. However, most of these studies have been concerned with supplementary vitamin C; the effects of under vitamin C insufficiency, which humans sometimes confront, have not been substantially investigated. In the present study, we established a vitamin C-insufficient animal model (half-to-normal serum vitamin C concentration) with gulo(-/-) mice that cannot synthesize vitamin C, and induced hepatotoxicity by means of thioacetamide (TAA) injections twice a week for 18 weeks. Additionally, we explored the direct effects of vitamin C both on immortalized human hepatic stellate LX-2 cells and on rat primary hepatic stellate cells. Vitamin C insufficiency resulted in a decreased survival rate and increased serum markers for hepatocyte damage, such as alanine aminotransferase and aspartate aminotransferase. Concomitantly, the levels of reactive oxygen species (ROS) and lipid peroxides in the liver were increased. Histological examinations of the vitamin C-insufficient liver revealed increases in collagen fiber deposition and activated-hepatic-stellate-cell number. Vitamin C, when directly applied to the LX-2 cells as well as the rat primary hepatic stellate cells, suppressed not only proliferation but hydrogen peroxide-induced collagen expression as well. In conclusion, vitamin C insufficiency exacerbated TAA-induced hepatotoxicity. These effects seem to be mainly from insufficient scavenging of ROS in the liver, and possibly in part, by directly affecting hepatic stellate cells.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Jun-Man
authors.initials: JM
authors.lastname: Hong
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea. Electronic address: hyi830@snu.ac.kr.
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Hwang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001206:Ascorbic Acid Deficiency / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001219:Aspartate Aminotransferases / Q000097:blood; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050544:L-Gulonolactone Oxidase / Q000172:deficiency / Q000235:genetics*; D015227:Lipid Peroxidation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013853:Thioacetamide
chemical_list: D017382:Reactive Oxygen Species; D013853:Thioacetamide; D003094:Collagen; D050544:L-Gulonolactone Oxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001205:Ascorbic Acid
keywords: Hepatic stellate cells; Hepatotoxicity; Lipid peroxidation; Reactive oxygen species; TGF-β1