Is This the Time to Reconsider the Names for Xenobiotic Nuclear Receptors?
Authors: Bo Kong, Grace L. Guo
Journal: Hepatology (2018)

SEE ARTICLE ON PAGE 343 Pregnane X receptor (PXR) has been known as a xenobiotic nuclear receptor and transcriptional factor that is important for inducing the expression of genes involved in drug disposition.1 Recently, PXR has emerged to critically regulate endobiotic metabolism, including the homeostasis of glucose, lipids, steroids, bile acids, bilirubin, retinoids, and bone minerals, and may be implicated in the treatment of cholestasis, inflammatory bowel disease, and nonalcoholic fatty liver diseases.3 PXR activation is also well known to increase liver size and cause liver hypertrophy. However, only a few studies have explored the role of PXR in liver regeneration and regrowth4; moreover, the exact mechanism by which PXR induces liver growth, especially how it interacts with the machinery of cellular proliferation, remains unclear. The study by Jiang et al.6 elegantly provides a novel mechanism by which PXR activation induces liver hypertrophy and hepatocyte proliferation. In this study, it was first confirmed that both mouse and human PXR activation could increase liver size, regardless of the species differences in ligand selectivity, highly suggesting that promoting liver growth by PXR activation is a human‐relevant issue to address. Intriguingly, it was shown that PXR activation increased the reprogramming of periportal hepatocytes to hybrid hepatocytes that are positive for both hepatocyte nuclear factor 4α and sex‐determining region Y box 9. This reprogramming promoted by PXR activation is a very novel finding. Finally, the activation of PXR not only increased Yes‐associated protein (Yap) mRNA levels but also increased nuclear translocation of YAP. Interestingly, the up‐regulation of YAP signaling seems not to follow the classical pathway by which YAP activation (through dephosphorylation) is inhibited by the cascade composed of the phosphorylated mammalian Ste20‐like kinase 1/2 and last tumor suppressor 1/2; rather, PXR could bind to YAP directly, and activation of PXR released itself as well as YAP, resulting in up‐regulation of the expression of target genes of PXR and YAP, respectively. However, it seems that YAP is required for the liver enlargement effect following PXR activation but not for the induction of drug‐metabolizing enzymes as knockdown of YAP in PXR‐activated mice only failed to increase liver size, without loss of the ability to induce drug‐metabolizing enzymes, suggesting that interaction with YAP is not required for PXR to regulate its specific target genes involved in drug disposition (Fig. 1).Figure 1: A novel mechanism of PXR in promoting liver size is by promoting YAP nuclear translocation by direct interaction. Abbreviations: LAST1/2, last tumor suppressor 1/2; MST1/2, mammalian Ste20‐like kinase 1/2; TAZ, transcriptional coactivator with a PDZ‐binding domain.YAP was first identified as a yes tyrosine kinase–associated protein and was the first protein identified to contain the WW domain, which recognizes a proline‐rich domain in various proteins.7 YAP does not bind to DNA directly but rather to a vast array of proteins and transcriptional factors to promote cell proliferation, endothelial to mesenchymal transition, and tumorigenesis. The only nuclear receptor that has been demonstrated to directly interact with YAP is peroxisome proliferator–activated receptor gamma.8 This study provides convincing evidence that PXR also physically interacts with YAP. More questions could be raised for initial discovery, for example, which domain(s) is responsible in the PXR protein for the interaction, whether ligand‐bound PXR is required, whether PXR binds to phosphorylated YAP or nonphosphorylated YAP, and, most importantly, which signal(s) channels PXR to induce drug‐metabolizing enzymes and/or to interact with the YAP pathway? Furthermore, whether the interaction between PXR and YAP requires the presence of the common YAP partner, transcriptional coactivator with a PDZ‐binding domain, is unclear. Many of the PXR target genes are also subject to the regulation of another xenobiotic nuclear receptor, constitutive androstane receptor (CAR). Activation of CAR results in marked induction of the expression of genes in drug disposition and a potent increase in liver size and hepatocyte hypertrophy. Kowalik et al. showed that activation of CAR increased nuclear translocation of YAP, which, for the first time, suggests the interaction of the xenobiotic nuclear receptor family member with the Hippo–YAP pathway.9 Furthermore, Abe et al. showed that knockdown or pharmacological inhibition of YAP drastically diminished the CAR‐dependent cell growth and induction of the cell proliferation marker genes.10 Interestingly, similar to PXR, CAR activation–induced cell proliferation and drug disposition are also detached, as shown by a recent publication from Bhushan et al.11 However, a direct physical interaction between CAR and YAP has not been determined from these studies. In summary, this is a significant and novel study that provides convincing evidence to link xenobiotic metabolism and endobiotic homeostasis. This study together with the recent publications regarding the roles of xenobiotic receptors in endobiotic metabolism prompt us to reconsider the major functions of PXR and CAR as solely xenobiotic nuclear receptors. The findings from this study may exert a profound influence on future studies of liver physiology, pathology, and pharmacology. Potential conflict of interest Dr. Guo consults for Metacrine.