Pterostilbene prevents hepatocyte epithelial‐mesenchymal transition in fructose‐induced liver fibrosis through suppressing miR‐34a/Sirt1/p53 and TGF‐β1/Smads signalling

Abstract

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‐β1 (TGF‐β1)/ Smads 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‐β1/Smads signalling, whereas these disturbances were suppressed by miR‐34a inhibitor. Additionally, miR‐34a inhibitor and p53 siRNA prevented TGF‐β1‐driven hepatocyte EMT under fructose exposure. Pterostilbene down‐regulated miR‐34a, up‐regulated Sirt1, and suppressed p53 activation and TGF‐β1/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‐β1/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.