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Identification of RARRES1 as a core regulator in liver fibrosis

Abstract:

Genetic factors contribute to progression and modulation of hepatic fibrosis. High throughput genomics/transcriptomics approaches aiming at identifying key regulators of fibrosis development are tainted with the difficulty of separating essential biological "driver" from modifier genes. We applied a comparative transcriptomics approach and investigated fibrosis development in different organs to identify overlapping expression changes, since these genes may be part of core pathways in fibrosis development. Gene expression was analysed on publicly available microarray data from liver, lung and kidney fibrosis. RARRES1, AGER and S100A2 were differentially regulated in all fibrosis experiments. RARRES1 was extensively analysed by means of advanced bioinformatics analyses and functional studies. Microarray and Western Blot analysis of a standard liver fibrosis model (CCl(4)) demonstrated an early induction of RARRES1 mRNA and protein expression. In addition, quantitative RT-PCR in tissue samples from patients with advanced liver fibrosis showed higher expression as compared to non-fibrotic biopsies. Microarray analysis of RARRES1 overexpressing cells identified an enrichment of a major signature associated with fibrosis. Furthermore, RARRES1 expression increased during in vitro activation of hepatic stellate cells. To further verify the pro-fibrogenic role across organs, we demonstrated an increase in RARRES1 expression in a rat lung fibrosis model induced by adenoviral TGF-β1 induction. We have performed a comparative transcriptomics analysis in order to identify core pathways of liver fibrogenesis, confirmed a candidate gene and enlightened the up- and downstream mechanisms of its action leading to fibrosis across organs and species.

22669512

Projects: B2.1: Hepatic stellate cells as source and target for hepatocellular gro...

Journal of molecular medicine (Berlin, Germany)
J. Mol. Med. 90(12): 1439-47
6th Jun 2012

Andreas Teufel, Diana Becker, Susanne N Weber, Steven Dooley, Katja Breitkopf-Heinlein, Thorsten Maass, Katrin Hochrath, Markus Krupp, Jens U Marquardt, Martin Kolb, Bernhard Korn, Christof Niehrs, Tim Zimmermann, Patricio Godoy, Peter R Galle, Frank Lammert

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[Steven Dooley] [Katja Breitkopf-Heinlein] [Patricio Godoy]

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Views: 1655
  • Created: 31st Jul 2012 at 11:24
  • Last updated: 24th Oct 2013 at 16:16

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