Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice

Hyon Seung Yi, Hyuk Soo Eun, Young-Sun Lee, Ju Yeon Jung, Seol Hee Park, Keun Gyu Park, Hueng Sik Choi, Jae Myoung Suh, Won Il Jeong

Research output: Contribution to journalArticle

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Abstract

Background & Aims: 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.

Original languageEnglish
Article numbere0127946
JournalPloS one
Volume10
Issue number5
DOIs
Publication statusPublished - 2015 May 29

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liver cirrhosis
natural killer cells
Natural Killer Cells
Liver Cirrhosis
Liver
Hepatic Stellate Cells
Vitamin A
liver
vitamin A
mice
Alcohol Dehydrogenase
alcohol dehydrogenase
cells
bile ducts
Metabolism
Ducts
Bile Ducts
Enzyme inhibition
Therapeutics
Ligation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice. / Yi, Hyon Seung; Eun, Hyuk Soo; Lee, Young-Sun; Jung, Ju Yeon; Park, Seol Hee; Park, Keun Gyu; Choi, Hueng Sik; Suh, Jae Myoung; Jeong, Won Il.

In: PloS one, Vol. 10, No. 5, e0127946, 29.05.2015.

Research output: Contribution to journalArticle

Yi, Hyon Seung ; Eun, Hyuk Soo ; Lee, Young-Sun ; Jung, Ju Yeon ; Park, Seol Hee ; Park, Keun Gyu ; Choi, Hueng Sik ; Suh, Jae Myoung ; Jeong, Won Il. / Treatment with 4-methylpyrazole modulated stellate cells and natural killer cells and ameliorated liver fibrosis in mice. In: PloS one. 2015 ; Vol. 10, No. 5.
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AU - Eun, Hyuk Soo

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AU - Jung, Ju Yeon

AU - Park, Seol Hee

AU - Park, Keun Gyu

AU - Choi, Hueng Sik

AU - Suh, Jae Myoung

AU - Jeong, Won Il

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