RT Journal Article
T1 Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice
A1 Bangen, Jörg-Martin
A1 Hu, Wei
A1 Haas, Ute
A1 Weiskirchen, Ralf
A1 Gassler, Nikolaus
A1 Huss, Sebastian
A1 Tacke, Frank
A1 Sicinski, Piotr
A1 Trautwein, Christian
A1 Liedtke, Christian
A1 Nevzorova, Yulia
AB Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl(4). To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1(-/-) and CcnE2(-/-) knock-out mice with CCl(4) to induce liver fibrosis. Interestingly, CcnE1(-/-) mice were protected against CCl(4)-mediated liver fibrogenesis, as evidenced by reduced collagen type I α1 expression and the lack of septum formation. In contrast, CcnE2(-/-) mice showed accelerated fibrogenesis after CCl(4) treatment. We isolated primary HSCs from WT, CcnE1(-/-), and CcnE2(-/-) mice and analyzed their activation, proliferation, and survival in vitro. CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1(-/-) HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells.Conclusions: CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis.
PB Lippincott, Williams & Wilkins
SN 0270-9139
YR 2012
FD 2012-09
LK https://hdl.handle.net/20.500.14352/97897
UL https://hdl.handle.net/20.500.14352/97897
LA eng
NO Nevzorova YA, Bangen JM, Hu W, Haas U, Weiskirchen R, Gassler N, Huss S, Tacke F, Sicinski P, Trautwein C, Liedtke C. Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice. Hepatology. 2012 Sep;56(3):1140-9. doi: 10.1002/hep.25736. Epub 2012 Jul 12. PMID: 22454377; PMCID: PMC3396430.
NO 1Department of Medicine III, University Hospital, RWTH Aachen, Pauwelsstrasse 30, D-52074Aachen, Germany2Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, RWTH Aachen,Pauwelsstrasse 30, D-52074 Aachen, Germany3Institute of Pathology, University Hospital, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen,Germany4Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, D-53123 Bonn,Germany5Department of Genetics, Harvard Medical School, Dana-Farber Cancer Institute, 450 BrooklineAve, Boston, MA 02215, USA
NO e Deutsche Forschungsgemeinschaft (DFG)
DS Docta Complutense
RD 19 abr 2025