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<p>Bile acids (BAs) flow through ducts lined by biliary epithelial cells (BECs), which preserve ductal integrity and liver homeostasis. Failure of this barrier causes BA accumulation in the liver parenchyma, and ultimately fibrosis. Here we show that BECs safeguard biliary barrier integrity and restrain BA-induced fibrogenesis through a cell-intrinsic mechanism involving farnesoid-X-receptor (FXR)–YAP signalling. Using a combination of mouse genetics, computational analysis and human samples, we show that BECs express FXR, which transcriptionally activates YAP to maintain their adhesion, thereby preventing BA efflux and subsequent FXR-dependent hepatic stellate cell activation and fibrosis in BA-dysregulated liver disease models. Genetic ablation of FXR or YAP in mouse BECs triggers β-catenin activation, mesenchymal-like conversion and BEC proliferation, promoting fibrosis-to-cirrhosis progression. Diminished FXR–YAP signalling in human BECs also parallels fibrosis severity. Consistently, obeticholic acid worsens fibrogenesis in mice with FXR-depleted BECs. Thus, BAs reprogram BECs into active guardians of tissue integrity via FXR–YAP–β-catenin signalling, preserving biliary identity and maintaining liver homeostasis.</p>

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FXR–YAP signalling maintains biliary epithelial cell identity and preserves liver homeostasis

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Paula Sánchez-Sánchez,
  • Zhaoshuo Wang,
  • Sladjana Zagorac,
  • María Domínguez,
  • Jasminka Boskovic,
  • Ajay Nair,
  • Andrea Macías-Camero,
  • Alma Villaseñor,
  • Robert F. Schwabe,
  • Nabil Djouder

摘要

Bile acids (BAs) flow through ducts lined by biliary epithelial cells (BECs), which preserve ductal integrity and liver homeostasis. Failure of this barrier causes BA accumulation in the liver parenchyma, and ultimately fibrosis. Here we show that BECs safeguard biliary barrier integrity and restrain BA-induced fibrogenesis through a cell-intrinsic mechanism involving farnesoid-X-receptor (FXR)–YAP signalling. Using a combination of mouse genetics, computational analysis and human samples, we show that BECs express FXR, which transcriptionally activates YAP to maintain their adhesion, thereby preventing BA efflux and subsequent FXR-dependent hepatic stellate cell activation and fibrosis in BA-dysregulated liver disease models. Genetic ablation of FXR or YAP in mouse BECs triggers β-catenin activation, mesenchymal-like conversion and BEC proliferation, promoting fibrosis-to-cirrhosis progression. Diminished FXR–YAP signalling in human BECs also parallels fibrosis severity. Consistently, obeticholic acid worsens fibrogenesis in mice with FXR-depleted BECs. Thus, BAs reprogram BECs into active guardians of tissue integrity via FXR–YAP–β-catenin signalling, preserving biliary identity and maintaining liver homeostasis.