miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis

被引:104
|
作者
Roderburg, Christoph [1 ]
Luedde, Mark [2 ]
Cardenas, David Vargas [1 ]
Vucur, Mihael [1 ]
Mollnow, Tobias [1 ]
Zimmermann, Henning W. [1 ]
Koch, Alexander [1 ]
Hellerbrand, Claus [3 ]
Weiskirchen, Ralf [4 ]
Frey, Norbert [2 ]
Tacke, Frank [1 ]
Trautwein, Christian [1 ]
Luedde, Tom [1 ]
机构
[1] Univ Aachen RWTH, Dept Med 3, D-52074 Aachen, Germany
[2] Univ Kiel, Dept Cardiol & Angiol, D-24105 Kiel, Germany
[3] Univ Regensburg, Dept Internal Med 1, D-93053 Regensburg, Germany
[4] Univ Aachen RWTH, Inst Clin Chem & Pathobiochem, D-52074 Aachen, Germany
基金
欧洲研究理事会;
关键词
miRNA; miR-133a; Hepatic stellate cells; TGF-beta; Liver fibrosis; miR-29; MYOCARDIAL FIBROSIS; MICRORNAS; MIR-29; EXPRESSION; REVEALS; CULTURE; RNAS;
D O I
10.1016/j.jhep.2012.11.022
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: miRNAs are novel regulators of organ fibrosis. miR-133a plays a role in cardiac and muscle remodeling, but its function in the liver is unclear. We therefore aimed at evaluating a possible function of miR-133a in hepatofibrogenesis. Methods: miR-133a levels were measured in whole liver samples from different murine hepatic fibrosis models and human liver tissue from patients with liver cirrhosis. The cell-specific regulation of miR-133a was assessed in FACS-sorted hepatic cell sub-populations. Murine and human primary hepatic stellate cells (HSC) were isolated and treated with different cytokines to evaluate upstream regulators of miR-133a. Moreover, GRX cells were transfected with synthetic miR-133a and the effect on extracellular matrix (ECM) gene regulation was assessed. Finally, miR-133a serum levels were measured in a cohort of patients with chronic liver diseases and correlated with disease progression. Results: Overall miR-133a expression levels were unchanged in whole RNA extracts from fibrotic murine and human livers. However, miR-133a was specifically downregulated in HSC during fibrogenesis. Treatment of primary murine and human HSC with transforming growth factor (TGF)-beta resulted in a significant downregulation of miR-133a in these cells. In turn, overexpression of miR-133a in primary murine HSC led to decreased expression of collagens. In addition, miR-133a serum levels were increased in patients with chronic liver disease and indicated the presence and progression of liver cirrhosis. Conclusions: Evidence is presented for a novel antifibrotic functional role of miR-133a in hepatofibrogenesis. miR-133a may thus represent a target for diagnostic and therapeutic strategies in liver fibrosis. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:736 / 742
页数:7
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