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Int J Med Sci. 2019 Jan 1;16(2):212-220. doi: 10.7150/ijms.29930. eCollection 2019.

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

Author information

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:

BRD4; bile duct ligation; cholestasis; liver fibrosis; miR-29a

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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