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

Christoph Roderburg, Mark Luedde, David Vargas Cardenas, Mihael Vucur, Tobias Mollnow, Henning W. Zimmermann, Alexander Koch, Claus Hellerbrand, Ralf Weiskirchen, Norbert Frey, Frank Tacke, Christian Trautwein, Tom Luedde

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

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 subpopulations. 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)-β 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.

Original languageEnglish
Pages (from-to)736-742
Number of pages7
JournalJournal of Hepatology
Volume58
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Keywords

  • Hepatic stellate cells
  • Liver fibrosis
  • TGF-β
  • miR-133a
  • miR-29
  • miRNA

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