Effect of dioscin on promoting liver regeneration via activating Notch1/Jagged1 signal pathway

Abstract

BackgroundDevelopment of novel candidates to promote liver regeneration is critical important after partial hepatectomy (PH). Dioscin, a natural product, shows potent effect on liver protection in our previous works. PurposeThis work aimed to investigate the effect and underlying mechanisms of dioscin on liver regeneration. MethodsThe promoting proliferation effects of dioscin on mouse hepatocytem AML12 cells, rat primary hepatocytes, rats and mice after 70% PH were evaluated. ResultsDioscin significantly promoted proliferation of rat primary hepatocytes and AML12 cells through MTT, BrdU and PCNA staining assays. Meanwhile, dioscin rapidly recovered the liver to body weight ratios, declined ALT and AST levels, and relieved hepatocytes necrosis compared with 70% PH operation groups in rats and mice. Mechanistic test showed that dioscin significantly increased Notch1 and Jagged1 levels, and accelerated γ-secretase activity by up-regulating PS1 expression, leading to nuclear translocation of Notch1 intracellular domain (NICD1). Subsequently, the significant activation of Notch-dependent target genes (Hey1, Hes1, EGFR, VEGF), and cell-cycle regulatory proteins (CyclinD1, CyclinE1, CDK4 and CDK2) were all recognized. In addition, these results were further confirmed by Notch1 siRNA silencing and inhibition of γ-secretase by DAPT (a well-characterized γ-secretase inhibitor) in vitro. ConclusionsDioscin, as a novel efficient γ-secretase activator, NICD1 nucleus translocation promoter and cell cycle regulator, markedly activated Notch1/Jagged1 pathway to promote hepato-proliferation. Our findings provide novel insights into dioscin as a natural product with facilitating liver regeneration after PH.