Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.

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 th...

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Autores principales:	Yixiong Chen, Shaoping Zheng, Dan Qi, Shaojiang Zheng, Junli Guo, Shuling Zhang, Zhihong Weng
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd589a7ff140419dab8bec455b1642cb
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spelling	oai:doaj.org-article:cd589a7ff140419dab8bec455b1642cb2021-11-18T08:13:21ZInhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.1932-620310.1371/journal.pone.0046512https://doaj.org/article/cd589a7ff140419dab8bec455b1642cb2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23056328/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Notch 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 (CCl(4)), 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.Yixiong ChenShaoping ZhengDan QiShaojiang ZhengJunli GuoShuling ZhangZhihong WengPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e46512 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yixiong Chen Shaoping Zheng Dan Qi Shaojiang Zheng Junli Guo Shuling Zhang Zhihong Weng Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
description	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 (CCl(4)), 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.
format	article
author	Yixiong Chen Shaoping Zheng Dan Qi Shaojiang Zheng Junli Guo Shuling Zhang Zhihong Weng
author_facet	Yixiong Chen Shaoping Zheng Dan Qi Shaojiang Zheng Junli Guo Shuling Zhang Zhihong Weng
author_sort	Yixiong Chen
title	Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
title_short	Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
title_full	Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
title_fullStr	Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
title_full_unstemmed	Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
title_sort	inhibition of notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/cd589a7ff140419dab8bec455b1642cb
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Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.

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