Notch signaling mediates liver fibrogensis

Background & Aims: Notch signaling is crucial in the development of metazoans, determining cell fate, and is directly linked to multiple human disorders, including Alagille syndrome in liver. We hypothesized that the Notch signaling pathway participates in liver fibrogenesis. Methods: Notch receptor and ligand expression in human and mouse livers were evaluated by immunohistochemistry and western blot. The effect of Notch signaling inhibitor was examined in hepatic stellate cells (HSCs). Results: In 2-weeks bile duct ligated mice, expression of Notch receptors (Notch-2, -3 and -4) and ligands (Jagged-1 and Jagged-2) were significantly increased in liver when compared to sham operated mice, as measured by immunohistochemistry and Western blot analysis. Consistent with findings in the mouse model, Western blot and/or immunohistochemistry analyses demonstrated enhanced Notch-2, Notch-3, Notch-4 and Jagged-1 expression in 43 liver tissues with HCV infection as compared to 5 normal liver tissues. In addition, immunohistochemical staining showed overexpression of Notch-2, Notch-3, Notch-4, Jagged-1, Delta-3, and Delta-4 in 80 HBV infected liver tissues. In vitro, g-secretase inhibitor (GSI), a general Notch signaling inhibitor, markedly decreased TGF-beta induced mRNA expression of collagen I and protein expression of a-smooth muscle actin, and connective tissue growth factor in rat hepatic stellate cells (HSCs). Moreover, TGF-beta induced Ad(CAGA) 9 -MLP-Luc reporter gene activity was significantly attenuated by GSI treatment in HSCs, indicating a crosstalk between Notch and TGF-beta signaling. Conclusions: Notch signaling participates in liver fibrogenesis. One mechanism is via contributing to activation and extracelluar matrix production of HSC . 244