PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor

Ryota Shizu, Taiki Abe, Satoshi Benoki, Miki Takahashi, Susumu Kodama, Masaaki Miayata, Atsushi Matsuzawa, Kouichi Yoshinari

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Growth factor-mediated hepatocyte proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnaneXreceptor (PXR), is a key transcription factor for the xenobiotic-induced expression of genes associated with various liver functions. Recently, we reported that PXR activation stimulates xenobiotic-induced hepatocyte proliferation. In the present study, we investigated whether PXR activation also stimulates growth factor-mediated hepatocyte proliferation. In G0 phase-synchronized, immortalized mouse hepatocytes, serum or epidermal growth factor treatment increased cell growth and this growth was augmented by the expression of mouse PXR and co-treatment with pregnenolone 16a-carbonitrile (PCN), a PXR ligand. In a liver regeneration model using carbon tetrachloride, PCN treatment enhanced the injury-induced increase in the number of Ki-67-positive nuclei as well as Ccna2 and Ccnb1 mRNA levels in wild-type (WT) but not Pxrnull mice. Chronological analysis of this model demonstrated that PCN treatment shifted the maximum cell proliferation to an earlier time point and increased the number of M-phase cells at those time points. In WT but not Pxr-null mice, PCN treatment reduced hepatic mRNA levels of genes involved in the suppression of G0/G1- and G1/S-phase transition, e.g. Rbl2, Cdkn1a and Cdkn1b. Analysis of the Rbl2 promoter revealed that PXR activation inhibited its Forkhead box O3 (FOXO3)- mediated transcription. Finally, the PXR-mediated enhancement of hepatocyte proliferation was inhibited by the expression of dominant active FOXO3 in vitro. The results of the present study suggest that PXR activation stimulates growth factor-mediated hepatocyte proliferation inmice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression.

Original languageEnglish
Pages (from-to)257-266
Number of pages10
JournalBiochemical Journal
Volume473
Issue number3
DOIs
Publication statusPublished - Feb 1 2016
Externally publishedYes

Keywords

  • Carbon tetrachloride
  • Cell cycle
  • Liver regeneration
  • Nuclear receptor
  • Xenobiotics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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  • Cite this

    Shizu, R., Abe, T., Benoki, S., Takahashi, M., Kodama, S., Miayata, M., Matsuzawa, A., & Yoshinari, K. (2016). PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor. Biochemical Journal, 473(3), 257-266. https://doi.org/10.1042/BJ20150734