Hepatic stellate cell FXR signaling regulates context-dependent functions in liver homeostasis and fibrosis.

Bile acids (BAs) are crucial in maintaining liver health and are a primary therapeutic target for fibrotic liver diseases. The farnesoid X receptor (FXR) is a key nuclear receptor that responds to BAs and is expressed in various liver cells, suggesting a role beyond the hepatocyte. A study explored the function of hepatic stellate cells' FXR (FXRHSC) in both healthy and injured livers.

FXR is present in both hepatocytes and stellate cells, but with different isoforms that have varying abilities to activate gene expression in the stellate cell context. The research found that a potent FXR agonist, tropifexor, initiates a gene expression program similar to that induced by partial hepatectomy, which stimulates hepatocyte proliferation.

This response was also seen in stellate cells and did not depend on FXR expression in the intestine. Furthermore, the study identified several FXR-responsive genes in stellate cells, including members of the glutathione-S-transferase family and Scube1. The FXRHSC alone was enough to produce anti-fibrotic effects in a precision-cut liver slice model, demonstrating the potential of targeting stellate cell FXR for treating fibrotic liver diseases.

Lastly, the researchers discovered that FXRHSC controls the expression of the chemerin gene, Rarres2, which plays a role in intercellular communication within the liver. These findings highlight the importance of FXRHSC in liver adaptation and its response to BAs, confirming that stellate cells are a significant site for nuclear bile acid signaling in liver biology.