Background & Aims: Mutation of Jagged-1 gene, a Notch ligand, leads to Alagille syndrome. However, patients
with Alagille syndrome usually do not progress into serious liver fibrosis. In the
present study, we investigated the role of Jagged-1 in liver fibrogenesis. Methods: Jagged-1 expression in diseased human and mouse livers were evaluated by immunohistochemistry
and Western blot. The effect of a Jagged-1 was examined in hepatic stellate cells
(HSCs). Results: Immunohistochemistry and Western blot analysis revealed that protein expression of
Jagged-1 in liver tissues from 2-week bile duct ligated mice was significantly increased
compared to sham operated mice. Consistently, enhanced Jagged-1 expression was found
in 80 HBV and 65 HCV patients, when compared to 5 normal liver samples by immunohistochemistry.
In vitro, a gamma-secretase inhibitor (GSI), representing a general inhibitor for
Notch receptor signaling, markedly decreased TGF-beta induced mRNA expression of collagen
I as well as protein expression of alpha-smooth muscle actin and connective tissue
growth factor (CTGF) in rat HSCs. Furthermore, knock-down of Jagged-1 by using siRNA
significantly decreased protein expression of collagen I and CTGF in CFSC cells, a
cell line from CCl4-induced cirrhotic rat HSCs. Conclusions: Jagged-1 plays a crucial role in liver fibrogenesis possibly via influencing activation
of HSCs and extracelluar matrix production.
CTGF - Hepatic stellate cell - Notch - alpha-smooth muscle actine - collagen
