Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice

Hyon Seung Yi, Young-Sun Lee, Jin Seok Byun, Wonhyo Seo, Jong Min Jeong, Ogyi Park, Gregg Duester, Takeshi Haseba, Sun Chang Kim, Keun Gyu Park, Bin Gao, Won Il Jeong

Research output: Contribution to journalArticle

30 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1044-1053
Number of pages10
JournalHepatology
Volume60
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

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Hepatic Stellate Cells
Natural Killer Cells
Liver Cirrhosis
Vitamin A
Alcohol Dehydrogenase
Transforming Growth Factors
Interferons
Enzymes
Collagen
Gene Expression
formaldehyde dehydrogenase (glutathione)
Carbon Tetrachloride
Therapeutics
Bile Ducts
Bone Marrow Transplantation
Genes
Ligation
Smooth Muscle
Actins
Hepatocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. / Yi, Hyon Seung; Lee, Young-Sun; Byun, Jin Seok; Seo, Wonhyo; Jeong, Jong Min; Park, Ogyi; Duester, Gregg; Haseba, Takeshi; Kim, Sun Chang; Park, Keun Gyu; Gao, Bin; Jeong, Won Il.

In: Hepatology, Vol. 60, No. 3, 01.01.2014, p. 1044-1053.

Research output: Contribution to journalArticle

Yi, HS, Lee, Y-S, Byun, JS, Seo, W, Jeong, JM, Park, O, Duester, G, Haseba, T, Kim, SC, Park, KG, Gao, B & Jeong, WI 2014, 'Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice', Hepatology, vol. 60, no. 3, pp. 1044-1053. https://doi.org/10.1002/hep.27137
Yi, Hyon Seung ; Lee, Young-Sun ; Byun, Jin Seok ; Seo, Wonhyo ; Jeong, Jong Min ; Park, Ogyi ; Duester, Gregg ; Haseba, Takeshi ; Kim, Sun Chang ; Park, Keun Gyu ; Gao, Bin ; Jeong, Won Il. / Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. In: Hepatology. 2014 ; Vol. 60, No. 3. pp. 1044-1053.
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AU - Jeong, Jong Min

AU - Park, Ogyi

AU - Duester, Gregg

AU - Haseba, Takeshi

AU - Kim, Sun Chang

AU - Park, Keun Gyu

AU - Gao, Bin

AU - Jeong, Won Il

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AB - 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. Conclusion: 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.

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