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

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ABSTRACT Nuclear bile acid (BA) signaling plays a central role in liver homeostasis and represents a major therapeutic axis in fibrotic liver diseases. The farnesoid X receptor (FXR), a master nuclear effector of BA signaling, is expressed in several liver-resident cell types, suggesting that it may regulate distinct biological programs beyond the hepatocyte (HC) compartment. Using complementary pharmacological, genetic, and computational approaches across in vitro, ex vivo, and in vivo models of mouse and human origin, we investigated the role of hepatic stellate cell (HSC) FXR (FXR HSC ) in both unchallenged and injured livers, which has remained controversial. FXRα is robustly expressed in both HCs and HSCs with distinct isoform distributions, and these isoforms exhibited differential capacities to activate gene expression in an HSC context. We found that the potent selective FXR agonist tropifexor triggers a transcriptional program reminiscent of that observed after partial hepatectomy and associated with HC proliferation. This cell cycle-related response was also observed in HSCs and did not require intestinal FXR expression. An HSC-specific response to tropifexor was observed for several genes, including members of the glutathione-S-transferase (GST) family or Scube1 . FXR HSC was sufficient to observe the anti-fibrotic effects of tropifexor in precisioncut liver slices, an ex-vivo model of fibrosis. Finally, we identified the regulation of the chemerin-encoding gene Rarres2 as a relevant example of FXR HSC -dependent control of hepatic intercellular communication. Together, these findings identify FXR HSC as an important contributor to hepatic adaptation and therapeutic response to BA analogs and confirmed HSCs as a significant site of nuclear bile acid signaling in liver biology.

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