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Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes‐Associated Protein Activation in Mice
Author(s) -
Jiang Yiming,
Feng Dechun,
Ma Xiaochao,
Fan Shicheng,
Gao Yue,
Fu Kaili,
Wang Ying,
Sun Jiahong,
Yao Xinpeng,
Liu Conghui,
Zhang Huizhen,
Xu Leqian,
Liu Aiming,
Gonzalez Frank J.,
Yang Yingzi,
Gao Bin,
Huang Min,
Bi Huichang
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30131
Subject(s) - pregnane x receptor , hepatocyte , nuclear receptor , microbiology and biotechnology , biology , hepatocyte nuclear factor 4 , receptor , liver regeneration , cell growth , endocrinology , medicine , transcription factor , regeneration (biology) , biochemistry , gene , in vitro
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 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 labeling using AAV‐ Tbg ‐Cre‐treated Rosa26 EYFP mice or Sox9‐Cre ERT , Rosa26 EYFP mice was performed and Pxr ‐null mice or AAV Yap short hairpin RNA (shRNA)‐treated mice were used to confirm the role of PXR or yes‐associated protein (YAP). Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild‐type (WT) 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 YAP and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR‐induced liver enlargement in mice. Conclusion : These findings revealed a function of PXR in enlarging liver size and changing liver cell fate by activation of the YAP signaling 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.