Cyclin E1 is an essential pro-fibrotic factor in the liver

E-Type cyclins E1 (CcnE1) and E2 (CcnE2) are important mediators for driving resting cells into the proliferative state of the cell cycle but are dispensable in continuously dividing cells. We recently showed that CcnE1 is a key player for hepatocyte proliferation during liver regeneration, whereas CcnE2 is essentially a regulator of CcnE1. Liver fibrogenesis is associated with proliferation of hepatocytes and hepatic stellate cells (HSC). Thus, the aim of this study was to investigate the potential contribution of CcnE1 for liver fibrosis in human and mice. Immunohistochemistry of human fibrotic liver sections displayed a significant increase of CcnE1 expression in hepatocytes and non-parenchymal cells hinting at a important role of CcnE1 in liver fibrosis. Accordingly, induction of liver fibrosis in wildtype (WT) mice by periodical administration of carbon tetrachloride (CCl 4 ) was also associated with induction of CcnE1 mRNA- and protein expression. Interestingly, the extend of liver fibrosis after CCl 4 treatment for 4 weeks was significantly lower in CcnE1-/- mice compared to WT controls. Expression of collagen1- and α-SMA mRNA in these mice was lower compared to the WT group and in situ staining of collagen1 and α-SMA revealed less fiber formation and reduced numbers of α-SMA positive cells in CcnE1-/- animals. Time course experiments in primary HSC derived from WT mice demonstrated that the CcnE expression peak is associated with onset of HSC proliferation and precedes transdifferentiation into myofibroblasts. In contrast, CcnE1-/- HSC showed incomplete cell cycle progression leading to S-phase arrest and strongly increased cell death. In summary, our results show an essential role of CcnE1 for fibrogenesis in man and mice and identify HSC as a target cell population for the pro-fibrogenic effect of CcnE1. cell cycle - cyclin E - fibrosis - hepatic stellate cells