Z Gastroenterol 2010; 48 - P380
DOI: 10.1055/s-0030-1263820

Contribution of E-type cyclins to hepatic fibrosis in human and mice

Y Nevzorova 1, JM Bangen 1, N Gassler 2, U Haas 1, W Hu 1, R Weiskirchen 3, F Tacke 1, P Sicinski 4, C Trautwein 1, C Liedtke 1
  • 1Department of Medicine III, University Hospital Aachen, Aachen, Germany
  • 2Institute of Pathology University Hospital Aachen, Aachen, Germany
  • 3Institute of Clinical Chemistry and Pathobiochemistry University Hospital Aachen, Aachen, Germany
  • 4Dana-Farber Cancer Institute, Boston, United States

Recent studies demonstrated that the E-type cyclins E1 (CcnE1) and E2 (CcnE2) are not essential for cell proliferation per se, but for transition of quiescent cells into the cell cycle. We recently showed that CcnE1 is a key player for hepatocyte proliferation during liver regeneration, while CcnE2 is a negative regulator of CcnE1.

The aim of this study was to investigate the potential contribution of CcnE1 for liver fibrosis in human and mice.

Increase of CcnE1 expression in hepatocytes and non-parenchymal cells in human fibrotic livers hinted at an important role of CcnE1 in liver fibrosis. Accordingly, administration of CCl4 to WT mice for 4 weeks resulted in prominent fibrosis and septum formation which was associated with significantly increased CcnE1 mRNA- and protein expression. In CcnE1–/– animals, the extend of liver fibrosis after CCl4 treatment was significantly lower and in situ staining revealed reduced numbers of α-SMA positive cells in these animals. As response on CCl4 treatment, CcnE2–/– mice presented earlier start of fiber formation.

Hepatic stellate cells (HSC) are thought to be an important mediator of liver fibrosis as they are activated upon pro-fibrotic stimuli, start proliferation and produce extracellular matrix. Time course experiments in primary HSC derived from WT mice demonstrated that CcnE1 is induced during activation of HSC. CcnE1 showed peak expression at the onset of HSC proliferation but clearly before transdifferentiation into myofibroblasts. In contrast, CcnE1– deficient HSC showed incomplete cell cycle progression leading to S-phase arrest and strongly increased cell death. Surprisingly, CcnE2–/– HSC showed accelerated and even earlier and prolonged a-SMA expression, which was correlated with high level of CcnE1.

In summary, our results show an essential role of CcnE1 for liver fibrogenesis in man and mice and identify HSC as a target cell population for the pro-fibrogenic effect of CcnE1, whereas CcnE2 apparently acts anti-fibrotic.