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

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.

Schisandrol B promotes liver regeneration after partial hepatectomy in mice.

Liver regeneration is a vital process of recovery after liver damage, which is a promising clinical strategy after partial hepatectomy (PHx). Schisandrol B (SolB), one of the bioactive ingredients from Schisandra sphenanthera, displays significant hepato-protection effects against drug-induced liver injure in mice. However, the effect of SolB on liver regeneration after PHx remains unclear. Here, we showed that SolB treatment promoted liver mass restoration and increased the number of proliferative hepatocytes following PHx. SolB treatment significantly improved the levels of growth factors (HGF and EGF) and cytokines (IL-6), which further activated STAT3/Akt/MAPK signaling pathways and induced the expression of several the protein of cell cycle core. Overall, this study is the first to demonstrate the role of SolB in promoting liver regeneration during PHx challenge, which provide a clinically relevant argument for using SolB to facilitate liver recovery after undergoing PHx or liver transplantation.