Deoxyelephantopin suppresses hepatic stellate cells activation associated with inhibition of aerobic glycolysis via hedgehog pathway

Abstract

Accumulating evidence suggests that hepatic stellate cells (HSCs) adopt aerobic glycolysis during activation. Hedgehog (Hh) pathway plays a vital role in the process of HSCs activation by regulating metabolism, and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone from Elephantopus scaber, has been shown to exert hepatoprotective as well as anticancer effects. However, the effect of DET on hepatic fibrosis and glycolysis in HSCs have never been elucidated. Here, we studied the function of the DET on HSCs activation and investigated the anti-fibrogenic effects of DET was associated with interfering with glycolysis in HSCs. Our results first demonstrated that DET reduced the expression of a-smooth muscle actin (a-SMA) and a1(I)procollagen at both mRNA and protein levels, and restore lipogenesis in HSCs. Furthermore, DET decreased the expression of hexokinase (HK), phosphofructokinase-2 (PFK2), Glucose transporter 4 (Glut4), and reduced lactate production dose-dependently in HSCs. Moreover, we further revealed that DET reduced fibrotic gene expression, restored lipid accumulation in HSCs. However, the Hh pathway agonist SAG could reverse the above effect of DET. Together, these results indicate DET inhibits aerobic glycolysis in HSCs associated with inhibition of Hh pathway. Our results provided a novel mechanism for DET suppression of HSC activation implicated in antifibrotic therapy.