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Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling.
Br J Pharmacol. 2019 06; 176(11):1619-1634.BJ

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.

Authors+Show Affiliations

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30632134

Citation

Song, Lin, et al. "Pterostilbene Prevents Hepatocyte Epithelial-mesenchymal Transition in Fructose-induced Liver Fibrosis Through Suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads Signalling." British Journal of Pharmacology, vol. 176, no. 11, 2019, pp. 1619-1634.
Song L, Chen TY, Zhao XJ, et al. Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling. Br J Pharmacol. 2019;176(11):1619-1634.
Song, L., Chen, T. Y., Zhao, X. J., Xu, Q., Jiao, R. Q., Li, J. M., & Kong, L. D. (2019). Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling. British Journal of Pharmacology, 176(11), 1619-1634. https://doi.org/10.1111/bph.14573
Song L, et al. Pterostilbene Prevents Hepatocyte Epithelial-mesenchymal Transition in Fructose-induced Liver Fibrosis Through Suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads Signalling. Br J Pharmacol. 2019;176(11):1619-1634. PubMed PMID: 30632134.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pterostilbene prevents hepatocyte epithelial-mesenchymal transition in fructose-induced liver fibrosis through suppressing miR-34a/Sirt1/p53 and TGF-β1/Smads signalling. AU - Song,Lin, AU - Chen,Tian-Yu, AU - Zhao,Xiao-Juan, AU - Xu,Qiang, AU - Jiao,Rui-Qing, AU - Li,Jian-Mei, AU - Kong,Ling-Dong, Y1 - 2019/04/24/ PY - 2018/02/05/received PY - 2018/10/22/revised PY - 2018/11/06/accepted PY - 2019/1/12/pubmed PY - 2020/9/1/medline PY - 2019/1/12/entrez SP - 1619 EP - 1634 JF - British journal of pharmacology JO - Br J Pharmacol VL - 176 IS - 11 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/30632134/Pterostilbene_prevents_hepatocyte_epithelial_mesenchymal_transition_in_fructose_induced_liver_fibrosis_through_suppressing_miR_34a/Sirt1/p53_and_TGF_β1/Smads_signalling_ L2 - https://doi.org/10.1111/bph.14573 DB - PRIME DP - Unbound Medicine ER -