Hepatic stellate cell FXR signaling regulates context-dependent functions in liver homeostasis and fibrosis.
- 1INSERM
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 (FXRHSC) in both unchallenged and injured livers, which has remained controversial. FXR 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. FXRHSC was sufficient to observe the anti-fibrotic effects of tropifexor in precision-cut liver slices, an ex-vivo model of fibrosis. Finally, we identified the regulation of the chemerin-encoding gene Rarres2 as a relevant example of FXRHSC-dependent control of hepatic intercellular communication. Together, these findings identify FXRHSC 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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BibTeX
@misc{vinod2026hepatic,
title = {{Hepatic stellate cell FXR signaling regulates context-dependent functions in liver homeostasis and fibrosis.}},
author = {M. Vinod and F.-P. Zummo and C. Gheeraert and Z. Gouda and S. Courquet and E. Dorchies and L. Thuret and M. Lapage and L. Guille and M. Bobowski-Gerard and C. Pourpe and V. Launay and M. Derhoudi and A. Bonnefond and D. Eberle and J. Haas and J. Dubois-Chevalier and J. Eeckhoute and S. Lestavel and B. Staels and P. Lefebvre and A. Berthier},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.29.747537},
url = {https://www.biorxiv.org/content/10.64898/2026.08.29.747537v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Hepatic stellate cell FXR signaling regulates context-dependent functions in liver homeostasis and fibrosis.
AU - M. Vinod
AU - F.-P. Zummo
AU - C. Gheeraert
AU - Z. Gouda
AU - S. Courquet
AU - E. Dorchies
AU - L. Thuret
AU - M. Lapage
AU - L. Guille
AU - M. Bobowski-Gerard
AU - C. Pourpe
AU - V. Launay
AU - M. Derhoudi
AU - A. Bonnefond
AU - D. Eberle
AU - J. Haas
AU - J. Dubois-Chevalier
AU - J. Eeckhoute
AU - S. Lestavel
AU - B. Staels
AU - P. Lefebvre
AU - A. Berthier
PY - 2026
DA - 2026/08/29
PB - bioRxiv
DO - 10.64898/2026.08.29.747537
UR - https://www.biorxiv.org/content/10.64898/2026.08.29.747537v1
AB - 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 (FXRHSC) in both unchallenged and injured livers, which has remained controversial. FXR 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. FXRHSC was sufficient to observe the anti-fibrotic effects of tropifexor in precision-cut liver slices, an ex-vivo model of fibrosis. Finally, we identified the regulation of the chemerin-encoding gene Rarres2 as a relevant example of FXRHSC-dependent control of hepatic intercellular communication. Together, these findings identify FXRHSC 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.
ER -