Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling
Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling
复制标题
Pterostilbene 通过抑制 miR-34a/Sirt1/p53 和 TGF-β1/Smads 信号传导防止果糖诱导的肝纤维化中的肝细胞上皮间质转化
DOI：
10.1111/bph.14573
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发表时间：
2019-06-01
影响因子：
7.3
通讯作者：
Kong, Ling-Dong
中科院分区：
文献类型：
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作者：
Song, Lin;Chen, Tian-Yu;Kong, Ling-Dong
Background and Purpose Excessive fructose consumption is a risk factor for liver fibrosis. Pterostilbene protects against liver fibrosis. Here, we investigated the potential role and the mechanisms underlying the hepatocyte epithelial-mesenchymal transition (EMT) in fructose-induced liver fibrosis and protection by pterostilbene. Experimental Approach Characteristic features of liver fibrosis in 10% fructose-fed rats and EMT in 5 mM fructose-exposed BRL-3A cells with or without pterostilbene and the change of miR-34a/Sirt1/p53 and transforming growth factor-beta 1 (TGF-beta 1)/ signalling were examined. MiR-34a inhibitor, miR-34a minic, or p53 siRNA were used to explore the role of miR-34a/Sirt1/p53 signalling in fructose-induced EMT and the action of pterostilbene. Key Results Pterostilbene prevented fructose-induced liver injury with fibrosis in rats. Fructose caused hepatocyte undergoing EMT, gaining fibroblast-specific protein 1 and vimentin, and losing E-cadherin, effects attenuated by pterostilbene. Moreover, fructose induced miR-34a overexpression in hepatocytes with down-regulated Sirt1, increased p53 and ac-p53, and activated TGF-beta 1/Smads signalling, whereas these disturbances were suppressed by miR-34a inhibitor. Additionally, miR-34a inhibitor and p53 siRNA prevented TGF-beta 1-driven hepatocyte EMT under fructose exposure. Pterostilbene down-regulated miR-34a, up-regulated Sirt1, and suppressed p53 activation and TGF-beta 1/Smads signalling in fructose-stimulated animals and cells but showed no additional effects with miR-34a inhibitor on miR-34a/Sirt1/p53 signalling in fructose-exposed hepatocytes. Conclusions and Implications These results strongly suggest that activation of miR-34a/Sirt1/p53 signalling is required for fructose-induced hepatocyte EMT mediated by TGF-beta 1/Smads signalling, contributing to liver fibrosis in rats. Pterostilbene exhibits a protective effect against liver fibrosis at least partly through inhibiting miR-34a/Sirt1/p53 signalling activation.
