Taurocholic Acid Promotes Hepatic Stellate Cell Activation via S1PR2/p38 MAPK/YAP Signaling under Cholestatic Conditions

Background and aims: Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effect of bile acids on the activation of hepatic stellate cells (HSC) is unknown. This study investigated the effect of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms.

Methods: The immortalized HSCs, LX-2 and JS-1cells, were used for the in vitro study. In vivo, the adeno-associated virus AAV-sh-S1PR2, and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSC.

Results: S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during TCA stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013, and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCA-mediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK).

Conclusions: TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation which might be therapeutically relevant for targeting cholestatic liver fibrosis.

S1PR2; YAP; cholestatic liver fibrosis; hepatic stellate cells; Taurocholic acid.