title: Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice.
abstract: OBJECTIVE
  Accumulating evidence suggests that retinol and its metabolites are closely associated with liver fibrogenesis. Recently, we demonstrated that genetic ablation of alcohol dehydrogenase 3 (ADH3), a retinol metabolizing gene that is expressed in hepatic stellate cells (HSCs) and natural killer (NK) cells, attenuated liver fibrosis in mice. In the current study, we investigated whether pharmacological ablation of ADH3 has therapeutic effects on experimentally induced liver fibrosis in mice.
  
  
  METHODS
  Liver fibrosis was induced by intraperitoneal injections of carbon tetrachloride (CCl4) or bile duct ligation (BDL) for two weeks. To inhibit ADH3-mediated retinol metabolism, 10 μg 4-methylpyrazole (4-MP)/g of body weight was administered to mice treated with CCl4 or subjected to BDL. The mice were sacrificed at week 2 to evaluate the regression of liver fibrosis. Liver sections were stained for collagen and α-smooth muscle actin (α-SMA). In addition, HSCs and NK cells were isolated from control and treated mice livers for molecular and immunological studies.
  
  
  RESULTS
  Treatment with 4-MP attenuated CCl4- and BDL-induced liver fibrosis in mice, without any adverse effects. HSCs from 4-MP treated mice depicted decreased levels of retinoic acids and increased retinol content than HSCs from control mice. In addition, the expression of α-SMA, transforming growth factor-β1 (TGF-β1), and type I collagen α1 was significantly reduced in the HSCs of 4-MP treated mice compared to the HSCs from control mice. Furthermore, inhibition of retinol metabolism by 4-MP increased interferon-γ production in NK cells, resulting in increased apoptosis of activated HSCs.
  
  
  CONCLUSIONS
  Based on our data, we conclude that inhibition of retinol metabolism by 4-MP ameliorates liver fibrosis in mice through activation of NK cells and suppression of HSCs. Therefore, retinol and its metabolizing enzyme, ADH3, might be potential targets for therapeutic intervention of liver fibrosis.
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Hyuk Soo
authors.initials: HS
authors.lastname: Eun
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea; Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biology Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.affiliation: Lab of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
mesh_terms: D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001652:Bile Ducts / Q000601:surgery; D002251:Carbon Tetrachloride / Q000633:toxicity; D004195:Disease Models, Animal; D000077604:Fomepizole; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology*; D014801:Vitamin A / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D014801:Vitamin A; D007371:Interferon-gamma; D000077604:Fomepizole; D002251:Carbon Tetrachloride; D000426:Alcohol Dehydrogenase