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

• Published in: PloS one Vol. 10; no. 5; p. e0127946
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.05.2015; Public Library of Science (PLoS)
• Subjects: Ablation; Acids; Actin; Alcohol dehydrogenase; Alcohol Dehydrogenase - antagonists & inhibitors; Alcohol Dehydrogenase - metabolism; Alcohols; Animals; Apoptosis; Apoptosis - drug effects; Bile; Bile ducts; Bile Ducts - surgery; Biological response modifiers; Body weight; Bone morphogenetic proteins; Carbon tetrachloride; Carbon Tetrachloride - toxicity; Care and treatment; Collagen (type I); Development and progression; Disease Models, Animal; Fibrosis; Fomepizole; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatocytes; Immunology; Inhibition; Interferon; Interferon-gamma - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Male; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Muscles; Natural killer cells; Patient outcomes; Pharmacology; Pyrazoles - pharmacology; Risk factors; Rodents; Smooth muscle; Stellate cells; Transforming growth factor; Transforming growth factor-b1; Vitamin A; Vitamin A - metabolism; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127946

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. 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. 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. 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.