科研之友
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摘要
Background: Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease, the most common chronic liver disease in the U.S. Fibrosis, a common feature of NASH, results from the dysregulation of fibrogenesis in hepatic stellate cells (HSCs). In this study, we investigated whether astaxanthin (ASTX), a xanthophyll carotenoid, can inhibit fibrogenic effects of transforming growth factor beta 1 (TGF beta 1), a key fibrogenic cytokine, in HSCs. Methods: Reactive oxygen species (ROS) accumulation was measured in LX-2, an immortalized human HSC cell line. Quantitative realtime PCR, Western blot, immunocytochemical analysis, and in-cell Western blot were performed to determine mRNA and protein of fibrogenic genes, and the activation of Smad3 in TGF beta 1-activated LX-2 cells and primary mouse HSCs. Results: In LX-2 cells, ROS accumulation induced by tert-butyl hydrogen peroxide and TGF beta 1 was abolished by ASTX. ASTX significantly decreased TGF beta 1-induced alpha-smooth muscle actin (alpha-SMA) and procollagen type 1, alpha 1 (Col1A1) mRNA as well as alpha-SMA protein levels. Knockdown of Smad3 showed the significant role of Smad3 in the expression of alpha-SMA and CollAl, but not TGF beta 1, in LX-2 cells. ASTX attenuated TGF beta 1-induced Smad3 phosphorylation and nuclear translocation with a concomitant inhibition of Smad3, Smad7, TGF beta receptor I (T beta RI), and Mall expression. The inhibitory effect of ASTX on HSC activation was confirmed in primary mouse HSCs as evidenced by decreased mRNA and protein levels of alpha-SMA during activation. Conclusion: Taken together, ASTX exerted anti-fibrogenic effects by blocking TGF beta 1-signaling, consequently inhibiting the activation of Smad3 pathway in HSCs. General significance: This study suggests that ASTX may be used as a preventive/therapeutic agent to prevent hepatic fibrosis.
- 出版日期2015-1
