Caffeine mitigates experimental nonalcoholic steatohepatitis and the progression of thioacetamide-induced liver fibrosis by blocking the MAPK and TGF-β/Smad3 signaling pathways |
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Authors: | Eduardo E Vargas-Pozada Erika Ramos-Tovar Consuelo Acero-Hernández Irina Cardoso-Lezama Silvia Galindo-Gómez Víctor Tsutsumi Pablo Muriel |
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Institution: | 1. Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico;2. Postgraduate Studies and Research Section, School of Higher Education in Medicine-IPN, Apartado 11340 Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Mexico City, Mexico;3. Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Apartado 14-740 Mexico City, Mexico |
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Abstract: | Introduction and objectivesCaffeine consumption is associated with beneficial effects on hepatic disorders. The objectives of this study were to evaluate the antifibrotic effects of caffeine on experimental nonalcoholic steatohepatitis (NASH) induced with a high-fat, high-sucrose, high-cholesterol diet (HFSCD), as well as to evaluate the ability of caffeine to prevent the progression of experimental liver fibrosis induced by the administration of thioacetamide (TAA) in rats and explore the mechanisms of action.MethodsNASH and fibrosis were induced in rats by the administration of an HFSCD for 15 weeks, and liver fibrosis was induced by intraperitoneal administration of 200 mg/kg TAA 3 times per week, for 6 weeks. Caffeine was administered at a dose of 50 mg/kg body weight. The effects of diet, TAA, and caffeine on fibrosis were evaluated by biochemical and histological examinations. The profibrotic pathways were analyzed by western blotting and immunohistochemistry.ResultsRats exhibited liver fibrosis after HFSCD feeding and the administration of TAA. Caffeine could reduce the hepatic level of collagen and the fibrotic area in the liver. Caffeine prevented the progression of liver fibrosis by decreasing transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and alpha-smooth muscle actin (α-SMA) expression and by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and Smad3 phosphorylation.ConclusionsCaffeine attenuates NASH and the progression of liver fibrosis due to its antifibrotic effects and modulating the MAPK and TGF-β pathways. Therefore, caffeine could be a suitable candidate for treating liver diseases associated with fibrosis. |
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Keywords: | Caffeine Experimental NASH Thioacetamide Fibrosis MAPK TGF-β 4 carbon tetrachloride CTGF connective tissue growth factor ECM extracellular matrix ERK extracellular signal-regulated kinases HCC hepatocellular carcinoma HFSCD high-fat high-sucrose high-cholesterol diet HSC hepatic stellate cell IHC immunohistochemical JNK c-Jun N-terminal kinases MAPKs mitogen-activated protein kinases MMP metalloproteinase NASH nonalcoholic steatohepatitis NF-κB nuclear factor kappa B PBS phosphate-buffered saline SE standard error TAA thioacetamide TGF-β transforming growth factor-beta α-SMA alpha-smooth muscle actin |
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