International Journal of Medical Sciences

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17 January 2019

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Int J Med Sci 2019; 16(2):212-220. doi:10.7150/ijms.29930

Research Paper

MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation

Ying-Hsien Huang1, Hsing-Chun Kuo2,3,4,5, Ya-Ling Yang6✉, Feng-Sheng Wang7✉

1. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
2. Department of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan
3. Reseach Fellow, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
4. Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
5. Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan
6. Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 833
7. Core Laboratory for Phenomics & Diagnostics, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, 833

Abstract

MicroRNA-29a is a key regulon that regulates hepatic stellate cells (HSCs) and mitigates liver fibrosis. However, the mechanism by which it does so remains largely undefined. The inhibition of bromodomain-4 protein (BRD4) represents a novel therapeutic target in hepatic fibrosis. Therefore, the purpose of this study is to investigate the miR-29a regulation of BRD4 signaling in a bile duct-ligation (BDL) animal model with regard to developing cholestatic liver fibrosis. Hepatic tissue in miR-29a transgenic mice (miR-29aTg mice) displayed weak fibrotic matrix, as shown by α-smooth muscle actin staining within affected tissues compared to wild-type mice. miR-29a overexpression reduced the BDL exaggeration of BRD4 and SNAI1 expression. Increased miR-29a signaling caused the downregulation of EZH2, MeCP2, and SNAI1, as well as the upregulation of PPAR-γ expression, in primary HSCs. We further demonstrated that the administration of JQ1, a BRD4 inhibitor, could inhibit BRD4, C-MYC, EZH2, and SNAI1 expression, while both JQ1 and a miR-29a mimic could inhibit the migration and proliferation of HSCs. In short, our research demonstrates that miR-29a negatively regulates HSC activation by inhibiting BRD4 and EZH2 function, thus making it a promising target for the pharmacologic treatment of hepatic fibrosis.

Keywords: miR-29a, bile duct ligation, cholestasis, liver fibrosis, BRD4

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How to cite this article:
Huang YH, Kuo HC, Yang YL, Wang FS. MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation. Int J Med Sci 2019; 16(2):212-220. doi:10.7150/ijms.29930. Available from http://www.medsci.org/v16p0212.htm