AHR regulates liver enlargement and regeneration through the YAP signaling pathway

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligands that participates in many important physiological processes. Although AHR activation is associated with hepatomegaly, the underlying mechanism remains unclear. This study evaluated the effects of AHR activation on liver enlargement and regeneration in various transgenic mice and animal models. Activation of AHR by the non-toxic ligand YH439 significantly induced liver/body weight ratio in wild-type mice (1.37-fold) and AHR^{fl/fl.ALB-CreERT2} mice (1.54-fold). However, these effects not present in AHR^ΔHep mice. Additionally, the activation of AHR promotes hepatocyte enlargement (1.43-fold or 1.41-fold) around the central vein (CV) and increases number of Ki67⁺ cells (42.5-fold or 48.8-fold) around the portal vein (PV) in wild-type mice and AHR^{fl/fl.ALB-CreERT2} mice. In the 70 % partial hepatectomy (PHx) model, YH439 significantly induced hepatocyte enlargement (1.40-fold) and increased number of Ki67⁺ cells (3.97-fold) in AHR^{fl/fl.ALB-CreERT2} mice. However, these effects were not observed in AHR^ΔHep mice. Co-immunoprecipitation results suggested a potential protein-protein interaction between AHR and Yes-associated protein (YAP). Disruption of the association between YAP and transcription enhancer domain family member (TEAD) significantly inhibited AHR-induced liver enlargement and regeneration. Furthermore, AHR failed to induce liver enlargement and regeneration in YAP^ΔHep mice. Blocking the YAP signaling pathway effectively eliminated AHR-induced liver enlargement and regeneration. This study revealed the molecular mechanism of AHR regulation of liver size and regeneration through the activation of AHR-TEAD signaling pathway, thereby offering novel insights into the physiological role of AHR. These findings provide a theoretical foundation for the prevention and treatment of disorders associated with liver regeneration.