{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:20:07Z","timestamp":1787761207956,"version":"build-2784847793"},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:p>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 16\u03b1-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\u00a0vitro. 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.<\/jats:p>","DOI":"10.1042\/bj20150734","type":"journal-article","created":{"date-parts":[[2015,11,17]],"date-time":"2015-11-17T02:39:23Z","timestamp":1447727963000},"page":"257-266","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor"],"prefix":"10.1042","volume":"473","author":[{"given":"Ryota","family":"Shizu","sequence":"first","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiki","family":"Abe","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"},{"name":"Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan"},{"name":"Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Benoki","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"},{"name":"Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Kodama","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Miayata","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Matsuzawa","sequence":"additional","affiliation":[{"name":"Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Yoshinari","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan"},{"name":"Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2016,1,25]]},"reference":[{"key":"2021112216334503800_B1","doi-asserted-by":"publisher","first-page":"S45","DOI":"10.1002\/hep.20969","article-title":"Liver regeneration","volume":"43","author":"Fausto","year":"2006","journal-title":"Hepatology"},{"key":"2021112216334503800_B2","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/jcp.21172","article-title":"Liver regeneration","volume":"213","author":"Michalopoulos","year":"2007","journal-title":"J. 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