title: Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice.
abstract: The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-β1 (TGF-β1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-β1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis.
  
  
  CONCLUSIONS
  ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis.
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Byun
authors.forename: Wonhyo
authors.initials: W
authors.lastname: Seo
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Jeong
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Takeshi
authors.initials: T
authors.lastname: Haseba
authors.forename: Sun Chang
authors.initials: SC
authors.lastname: Kim
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation; D055166:Hepatic Stellate Cells / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D007371:Interferon-gamma; C020145:formaldehyde dehydrogenase (glutathione); D000445:Aldehyde Oxidoreductases