Geniposide, a sonic hedgehog signaling inhibitor, inhibits the activation of hepatic stellate cell

Abstract

Liver fibrosis is a continuous wound-healing process, which is due to excessive deposition of extracellular matrix (ECM) caused by activated Hepatic Stellate Cells (HSCs). Geniposide (GP) is a naturally occurring iridoid glucoside and is extracted from Gardenia jasminoides Ellis. GP has long been speculated to play a vital role in the treatment of hyperlipidemia and fatty liver. Emerging evidence has demonstrated that GP may be importantly associated with the pathophysiology of liver fibrosis. Nevertheless, the fundamental mechanism is yet uncertain. This studywas designed to explore the possible mechanism for the inhibitory effect of GP on CCl4-induced mice liver fibrosis. In line with several clinical reports, GP significantly reduced the levels of hyaluronic acid (HA), laminin (LN), hydroxyproline (HYP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Meanwhile, liver fibrosis was significantly alleviated by GP as indicated by decreased α-smooth muscle actin (α-SMA) expression and type I collagen alpha-1 (Col I α1) deposition. In addition, GP could reduce the cell viability (IC50 = 77.11 and 42.88 μM at 24 and 48 h respectively) and cause G2/M cell arrest of the activated HSC-T6 cells. Noteworthy, GP prominently suppressed the Sonic hedgehog (Shh) signaling pathway and it might inhibit the activation and proliferation of HSC-T6 cells through Shh signaling pathway. Taken together, the current research indicate that GP has a promising antifibrotic effect which could be partially attributed to its suppression of Shh signaling pathway. Hence GP could be employed as a promising therapeutic strategy for the treatment of clinical hepatic injury.