Pterostilbene exhibits a protective effect against liver fibrosis. - GreenMedInfo Summary
Pterostilbene prevents hepatocyte EMT in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signaling.
Br J Pharmacol. 2019 Jan 10. Epub 2019 Jan 10. PMID: 30632134
BACKGROUND AND PURPOSE: Excessive fructose consumption is a risk factor liver fibrosis. Pterostilbene shows anti-liver fibrosis activity. Here, we investigated the potential role and the mechanisms underlying hepatocyte epithelial-mesenchymal transition (EMT) in fructose-induced liver fibrosis, as well as the protection of pterostilbene.
EXPERIMENTAL APPROACH: The characteristics of liver fibrosis in 10% fructose-fed rats and EMT in 5 mM fructose-exposed BRL-3A cells with or without pterostilbene, as well as the change of miR-34a/Sirt1/p53 and transforming growth factorβ1 (TGF-β1)/Smads signaling, were examined. MiR-34a inhibitor, miR-34a minic or p53 siRNA were used to explore the role of miR-34a/Sirt1/p53 signaling 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 (FSP1) and vimentin, and losing E-cadherin, 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 signaling, 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 signaling in fructose-induced animals and cells, but showed no superimposed effect with miR-34a inhibitor on miR-34a/Sirt1/p53 signaling in fructose-exposed hepatocytes.
CONCLUSIONS AND IMPLICATIONS: These results strongly support that the activation of miR-34a/Sirt1/p53 signaling is required for fructose-induced hepatocyte EMT mediated by TGF-β1/Smads signaling, contributing to liver fibrosis in rats. Pterostilbene exhibits a protective effect against liver fibrosis at least partly through inhibiting miR-34a/Sirt1/p53 signaling activation.