☆ 4.5 Article

Astaxanthin prevents TGF beta 1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS (2015)

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BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

卷 1850, 期 1, 页码 178-185

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ELSEVIER SCIENCE BV

DOI: 10.1016/j.bbagen.2014.10.014

关键词

Astaxanthin; Non-alcoholic steatohepatitis; Liver fibrosis; Hepatic stellate cell; Transforming growth factor beta 1; Smad3

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Biochemistry & Molecular Biology Biophysics

资金

USDA AFRI [2012-67018-19290]
USDA Multi-state/Hatch [CONS00916]

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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. (C) 2014 Elsevier B.V. All rights reserved.

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Trimetazidine inhibits liver fibrosis and hepatic stellate cell proliferation and blocks transforming growth factor-β (TGFβ)/Smad signaling in vitro and in vivo

Wenwen Ding, Danhua Zhou, Shimeng Zhang, Jiaping Qian, Lingxia Yang, Lei Tang

Summary: This study demonstrates that Trimetazidine (TMZ) can inhibit liver fibrosis and hepatic stellate cell proliferation induced by CCl4 and TGF-beta. TMZ exerts its effects by blocking the activation of TGF beta/Smad signaling pathway. These findings provide new insights into the potential application of TMZ in the treatment of liver fibrosis.

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