title: Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes.
abstract: Although hepatic progenitor cells (HPCs) are known to contribute to cholestatic liver fibrosis (CLF), how Notch signaling modulates the differentiation of HPCs to cholangiocytes in CLF is unknown. Thus, using a rat model of CLF that is induced by bile duct ligation, we inhibited Notch signaling with DAPT. In vivo, CK19, OV6, Sox9, and EpCAM expression was increased significantly. Notch signaling increased after bile duct ligation, and DAPT treatment reduced the expression of CK19, OV6, Sox9, and EpCAM and blocked cholangiocyte proliferation and CLF. In vitro, treatment of a WB-F344 cell line with sodium butyrate resulted in increased mRNA and protein expression of CK19, Sox9, and EpCAM, but Notch signaling was activated. Both of these processes were inhibited by DAPT. This study reveals that Notch signaling activation is required for HPC differentiation into cholangiocytes in CLF, and inhibition of the Notch signaling pathway may offer a therapeutic approach for treating CLF.
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Guangli
authors.initials: G
authors.lastname: Du
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Li
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Chen
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Chenghai
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zern
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine; Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Ping
authors.identifier: http://orcid.org/0000-0002-6152-4508
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002779:Cholestasis / Q000150:complications*; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D051880:Receptors, Notch