Su1678 Autophagy As a Therapeutic Target for Rats With Hepatic Fibrosis

Abstract

Repair from hepatic injury involves re-activation of morphogenetic signaling pathways. Notch signaling controls cell differentiation and deregulation of the Notch pathway induces several types of diseases including these associated with pericyte. We hypothesized that Notch signaling regulates hepatic stellate cell (HSC, liver pericyte) transdifferentiation through cross-talk with other characterized signaling pathways that regulate HSCs activation, like the Hedgehog (Hh) pathway. We examined Notch signaling in two types of hepatic injury (bile duct ligation, and high fat diet with carbon tetrachloride-induced fibrosis). Immature ductular cells and primary HSCs were manipulated with the γ-secretase inhibitor DAPT to assess the role of Notch signaling in hepatic cell differentiation. To determine the effect of Hh signaling on Notch pathway, cells were treated with the Smoothened inhibitor GDC0449. Finally, Hh signaling was conditionally disrupted inmyofibroblasts in vivo to determine its effects on Notch signaling. Notch-2, Jagged-1 and various Notch target genes were induced in fibrotic liver injury at both mRNA and protein level. HSCs up-regulate both Notch receptor and ligand during culture-activation; DAPT inhibits Notch signaling, preventing activation, promoting quiescence and down-regulating Hh signaling. Similarly, Hh inhibition reduced Notch signaling both in vitro and in vivo. Conclusion: Notch and Hh signaling interact to controls HSC transdifferentiation during injury-induced activation.