Activated hepatic stellate cells maintain hepatic bile acid homeostasis through paracrine FGF10/FGFR2 signaling

Hepatic stellate cells (HSCs) are activated during cholestasis. However, beyond their role in liver fibrosis, whether HSCs influence bile acid (BA) synthesis and homeostasis remains largely unknown. This study investigates the role of activated HSCs (aHSCs) in the regulation of hepatic BA metabolism.

Human liver tissues, human primary HSCs, and hepatocytes were utilized in this study. Fgf10 knock-in reporter mice, aHSC-specific Fgf10 knockout mice, and hepatocyte-specific Fgfr2 knockdown mice were generated. Mouse models of obstructive cholestasis and western diet-induced MASH were established. Recombinant FGF10 was administered to further validate the role of the FGF10/FGFR2 axis in regulating BA homeostasis and fibrosis. Bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq were performed to elucidate how aHSCs regulate BA metabolism via FGF10.

FGF10 was upregulated in human fibrotic livers. The expression of FGF10 by aHSCs was increased in animal models of obstructive cholestasis and diet-induced MASH. Cholestasis-induced ductular reaction and tissue fibrosis were aggravated in livers of aHSC-specific Fgf10 knockout mice. RNA-seq and single-nucleus RNA-seq indicated that aHSCs regulate primary BA synthesis through FGF10-mediated CYP7A1 inhibition. Paracrine FGF10 induced the upregulation of FGFR2 in hepatocytes, resulting in the activation of PAK1/ERK/JNK signaling, thereby inhibiting CYP7A1 expression and the synthesis of primary BAs. In diet-induced MASH, FGF10 exerted no significant effect on steatosis or fibrosis but significantly influenced BA metabolism. Additionally, recombinant FGF10 treatment ameliorated cholestatic liver injury and reduced BA accumulation in mice, which was abrogated by Fgfr2 knockdown in hepatocytes.

This study identifies a critical role for aHSCs in the regulation of hepatic BA homeostasis and demonstrates that the aHSC-FGF10/FGFR2 signaling axis may represent a potential therapeutic target for cholestatic liver disease.

Cholestasis and metabolic dysfunction-associated steatohepatitis (MASH) are associated with the activation of hepatic stellate cells (HSCs), yet whether HSCs influence bile acid metabolism during these processes remains largely unknown. Here, we demonstrate that murine activated HSCs control CYP7A1 expression in hepatocytes via paracrine FGF10, which inhibits primary bile acid (BA) synthesis in obstructive cholestasis and MASH. Paracrine FGF10/FGFR2 signaling controlled hepatic primary BA synthesis and alleviated ductular reaction and liver injury in cholestatic mice, but showed no significant effect on steatosis and fibrosis during MASH progression. This study implies specific roles for activated HSCs and FGF10 in the maintenance of hepatic BA homeostasis.