Yiming Jiang1, Dechun Feng2, Xiaochao Ma3, Shicheng Fan1, Yue Gao1, Kaili Fu1, Ying Wang4, Jiahong Sun1, Xinpeng Yao1, Conghui Liu1, Huizhen Zhang1, Leqian Xu1, Aiming Liu5, Frank J Gonzalez6, Yingzi Yang7, Bin Gao2, Min Huang1, Huichang Bi1. 1. Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. 2. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. 3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA. 4. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. 5. Medical School of Ningbo University, Ningbo, China. 6. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 7. Harvard School of Dental Medicine, Boston, MA.
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 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 Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP 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.
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 Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP 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.
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