{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:31:18Z","timestamp":1792279878268,"version":"4.4.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin\u2010dependent kinase 2 (Cdk2) and controls cell cycle re\u2010entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)\u2010based approach. CcnE1\u2010siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL\/6 wild\u2010type (WT) mice, delivery of stabilized siRNA using a liposome\u2010based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45<jats:sup>+<\/jats:sup> cells after single injection. Acute CCl<jats:sub>4<\/jats:sub>\u2010mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45<jats:sup>+<\/jats:sup> leukocytes. Pretreatment with CcnE1\u2010siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes and leukocytes, and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl<jats:sub>4<\/jats:sub> for 4\u20106 weeks. Co\u2010treatment with CcnE1\u2010siRNA once a week was sufficient to continuously block CcnE1 expression and cell\u2010cycle activity of hepatocytes and nonparenchymal cells, resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1\u2010siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Therapeutic targeting of CcnE1 <jats:italic toggle=\"yes\">in vivo<\/jats:italic> using RNAi is feasible and has high antifibrotic activity. (H<jats:sc>epatology<\/jats:sc> 2017;66:1242\u20101257).<\/jats:p>","DOI":"10.1002\/hep.29275","type":"journal-article","created":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T08:49:30Z","timestamp":1495097370000},"page":"1242-1257","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":54,"title":["Targeting CCl4\u2010induced liver fibrosis by RNA interference\u2013mediated inhibition of cyclin E1 in mice"],"prefix":"10.1097","volume":"66","author":[{"given":"J\u00f6rg\u2010Martin","family":"Bangen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III,RWTH Aachen University,Aachen,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Hammerich","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III,RWTH Aachen 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