Inhibition of Notch Signaling by a γ-Secretase Inhibitor Attenuates Hepatic Fibrosis in Rats

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.

Cellular and molecular mechanisms in liver fibrogenesis

“…In addition, the relevance of Hedgehog and TGFβ1-Smad2/3 signaling was reported also in human patients [17,24]. More recently, Notch signalinghas been also implicated in EMT and liver fibrosis based on the reported action of the γ-secretase inhibitor DAPT that, by inhibiting Notch signaling, blocked an EMT-like transition in both primary mouse HSCs and a rat HSC cell line as well as inhibited HSC activation and attenuated CCl 4 -induced rat liver fibrosis [28,29]. Similar reports suggested the efficacy in blocking cholangiocyte EMT by using the same γ-secretase inhibitor or a Jagged1-neutralizing antibody [29,30].…”

Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway

“…Notch signaling occurs in a highly localized manner by interacting with neighboring cells. When a ligand binds to the Notch receptor, Notch undergoes two proteolytic cleavage events: it liberates the Notch intracellular domain to enter the nucleus, where it binds to the transcription factor RBPJK/CBF1/Su(H) and converts it from a repressor to an activator for target genes, including the Hes and Hey family genes [8]. The Notch signal pathway has attracted much attention in research into fibrosis formation and collagen regeneration.…”

Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells

“…Notably, Notch cleavage upstream of g-secretase is mediated by a disintegrin and metalloproteinase (ADAM) proteases, in particular by ADAM10 and ADAM17 (20). Interestingly, Notch/ Jagged signaling is critical for liver regeneration in response to partial hepatectomy (21), hepatic fibrogenesis (22), and hepatocellular carcinoma (23). Moreover, mutations in this pathway have been described in liver diseases associated with the Alagille syndrome (24).…”