Abstract
Notch signaling is essential to the regulation of cell differentiation, and aberrant activation of this pathway is implicated in human fibrotic diseases, such as pulmonary, renal, and peritoneal fibrosis. However, the role of Notch signaling in hepatic fibrosis has not been fully investigated. In the present study, we show Notch signaling to be highly activated in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4), as indicated by increased expression of Jagged1, Notch3, and Hes1. Blocking Notch signaling activation by a γ-secretase inhibitor, DAPT, significantly attenuated liver fibrosis and decreased the expression of snail, vimentin, and TGF-β1 in association with the enhanced expression of E-cadherin. The study in vitro revealed that DAPT treatment could suppress the EMT process of rat hepatic stellate cell line (HSC-T6). Interestingly, DAPT treatment was found not to affect hepatocyte proliferation in vivo. In contrast, DAPT can inhibit hepatocyte apoptosis to some degree. Our study provides the first evidence that Notch signaling is implicated in hepatic fibrogenesis and DAPT treatment has a protective effect on hepatocytes and ameliorates liver fibrosis. These findings suggest that the inhibition of Notch signaling might present a novel therapeutic approach for hepatic fibrosis.
Highlights
Hepatic fibrosis is a reversible wound-healing response characterized by the accumulation of extracellular matrix (ECM) in response to acute or chronic liver injury
Activation of Notch Signaling in a Rat Model of Liver Fibrosis Induced by CCl4
We show that Notch signaling is markedly activated in a rat model of liver fibrosis induced by CCl4
Summary
Hepatic fibrosis is a reversible wound-healing response characterized by the accumulation of extracellular matrix (ECM) in response to acute or chronic liver injury. The activation and proliferation of hepatic stellate cells (HSCs) has been identified as a critical event in the development of hepatic fibrosis. Activated HSCs are highly contractile and express a-smooth muscle actin (a-SMA) and ECM. They are a key target for anti-fibrotic therapies because these cells are the primary source of ECM in injured livers [2,3,4,5]. Notch signaling is activated through an interaction of a Notch receptor with a ligand expressed on adjacent cells leading to proteolytic cleavages of Notch receptor. The NICD moves to the nucleus, where it interacts with CSL (RBP-Jk/CBF1) and Mastermind to activate transcription of downstream target genes such as Hes (hairy and enhancer of split 1), HRT (hairy-related transcription), Deltes-1, Meltrin-b, and the Notch receptors themselves [17,18,19,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
