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: 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.
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Authors | 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 |
Journal | PloS one
(PLoS One)
Vol. 10
Issue 5
Pg. e0127946
( 2015)
ISSN: 1932-6203 [Electronic] United States |
PMID | 26024318
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Pyrazoles
- Vitamin A
- Interferon-gamma
- Fomepizole
- Carbon Tetrachloride
- Alcohol Dehydrogenase
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Topics |
- Alcohol Dehydrogenase
(antagonists & inhibitors, metabolism)
- Animals
- Apoptosis
(drug effects)
- Bile Ducts
(surgery)
- Carbon Tetrachloride
(toxicity)
- Disease Models, Animal
- Fomepizole
- Hepatic Stellate Cells
(drug effects, metabolism, pathology)
- Interferon-gamma
(metabolism)
- Killer Cells, Natural
(drug effects, metabolism)
- Liver Cirrhosis
(chemically induced, drug therapy, metabolism, pathology)
- Male
- Mice, Inbred C57BL
- Pyrazoles
(pharmacology)
- Vitamin A
(metabolism)
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