TY - JOUR T1 - Functional interaction between PXR and YAP in xenobiotic-dependent liver hypertrophy and drug metabolism JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.258632 SP - jpet.119.258632 AU - Taiki Abe AU - Ryota Shizu AU - Takamitsu Sasaki AU - Yuki Shimizu AU - Takuomi Hosaka AU - Susumu Kodama AU - Atsushi Matsuzawa AU - Kouichi YOSHINARI Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/09/18/jpet.119.258632.abstract N2 - Pregnane X receptor (PXR), a xenobiotic-responsive nuclear receptor, plays key roles in drug disposition. PXR activation induces liver hypertrophy in rodents, but the molecular mechanism of this effect remains unclear although the PXR-mediated induction of cytochrome P450s is proposed to be involved. Since yes-associated protein (YAP), an effector protein of the Hippo pathway, functions as a transcriptional cofactor that controls organ size via TEA domain family members (TEADs) or other transcription factors, we investigated the functional interaction of PXR with YAP in liver hypertrophy and drug metabolism in this study. The treatment of mice with a PXR activator induced liver hypertrophy, promoted nuclear YAP accumulation and increased the expression of YAP/TEAD target genes in the liver, suggesting the coactivation of PXR and YAP. Through chronological analyses of this in vivo model, no clear association between PXR-dependent liver hypertrophy and cytochrome P450 induction was observed. In reporter assays, ligand-activated PXR enhanced YAP-mediated gene transcription, whereas YAP overexpression inhibited PXR-dependent gene transcription. No clear species differences in these transcriptional interactions between humans and mice were observed. Furthermore, in human hepatocarcinoma and primary hepatocyte-like cells, YAP suppressed the expression of liver-enriched transcription factors, including hepatocyte nuclear factor 4α (HNF4α), PXR and constitutive androstane receptor (CAR), and their target genes. These results suggest that YAP is involved in PXR-induced liver hypertrophy and that YAP activation interferes with gene expression associated with various liver functions.SIGNIFICANCE STATEMENT We have investigated the functional interaction between PXR and YAP, an effector protein of the Hippo pathway. PXR plays central roles in various liver functions including drug metabolism, and the Hippo pathway and YAP regulate organ size through interacting with several transcription factors, including TEADs. Our results suggest that YAP is involved in PXR-mediated liver hypertrophy and that YAP activation interferes with the expression of liver-enriched transcription factors and thus drug-metabolizing enzymes. ER -