Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes‐Associated Protein Activation in Mice

Abstract

Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and the cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically-modified mice and animal models. Lineage labelling using AAV-Tbg-Cre-treated Rosa26 mice or Sox9-Cre , Rosa26 mice was performed and Pxr-null mice or AAV Yap shRNA-treated mice were used to confirm the role of PXR or YAP. Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type and PXR-humanized mice but not in Pxr-null mice by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with yes-associated protein (YAP) and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. These findings revealed a novel function of PXR in enlarging liver size and changing liver cell fate via activation of the YAP signalling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate. This article is protected by copyright. All rights reserved.

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