Growth factor-mediated hepatocyte proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnane X receptor (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 16α-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 Pxr-null 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 in mice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression.
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Point scanning confocal microscopic imaging of C2C12 undifferentiatedmyoblasts (top panels) and differentiatedmultinucleated myotubes (bottom panels) immunofluorescently labelled with DAPI (blue) PDLIM7 (green) and Phalloidin or Nedd4-1 (red). Merged images show co-localization of PDLIM7 and Phalloidin decreases with myotube formation (left panels) and co-location of PDLIM7 and Nedd4-1 increases with myotube formation (right panels). Image courtesy of Robert D’Cruz et al. (for further details see pages 267–276). - PDF Icon PDF LinkFront Matter
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Research Article|
January 25 2016
PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor
Ryota Shizu;
Ryota Shizu
1
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Taiki Abe;
Taiki Abe
1
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
†Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
‡Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Satoshi Benoki;
Satoshi Benoki
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Miki Takahashi;
Miki Takahashi
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
‡Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Susumu Kodama;
Susumu Kodama
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Masaaki Miayata;
Masaaki Miayata
2
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Atsushi Matsuzawa;
Atsushi Matsuzawa
‡Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
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Kouichi Yoshinari
Kouichi Yoshinari
3
*Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan
†Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
3To whom correspondence should be addressed (email: yoshinari@u-shizuoka-ken.ac.jp).
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Publisher: Portland Press Ltd
Received:
July 13 2015
Revision Received:
November 09 2015
Accepted:
November 16 2015
Accepted Manuscript online:
November 16 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 Authors; published by Portland Press Limited
2016
Biochem J (2016) 473 (3): 257–266.
Article history
Received:
July 13 2015
Revision Received:
November 09 2015
Accepted:
November 16 2015
Accepted Manuscript online:
November 16 2015
Citation
Ryota Shizu, Taiki Abe, Satoshi Benoki, Miki Takahashi, Susumu Kodama, Masaaki Miayata, Atsushi Matsuzawa, Kouichi Yoshinari; PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor. Biochem J 1 February 2016; 473 (3): 257–266. doi: https://doi.org/10.1042/BJ20150734
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