Role of the hepatocyte nuclear factor 4α in control of the pregnane X receptor during fetal liver development

HepatologyVolume 37, Issue 6 p. 1375-1384 Original ArticleFree Access Role of the hepatocyte nuclear factor 4α in control of the pregnane X receptor during fetal liver development Akihide Kamiya, Akihide Kamiya Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDSearch for more papers by this authorYusuke Inoue, Yusuke Inoue Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDSearch for more papers by this authorFrank J. Gonzalez Ph.D., Corresponding Author Frank J. Gonzalez Ph.D. [email protected] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDLaboratory of Metabolism, National Cancer Institute, National Institutes of Health, Building 37, Room 2A19, 9000 Rockville Pike, Bethesda, MD 20892; fax: 301-496-8419===Search for more papers by this author Akihide Kamiya, Akihide Kamiya Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDSearch for more papers by this authorYusuke Inoue, Yusuke Inoue Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDSearch for more papers by this authorFrank J. Gonzalez Ph.D., Corresponding Author Frank J. Gonzalez Ph.D. [email protected] Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MDLaboratory of Metabolism, National Cancer Institute, National Institutes of Health, Building 37, Room 2A19, 9000 Rockville Pike, Bethesda, MD 20892; fax: 301-496-8419===Search for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2003.50212Citations: 112AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract The fetal liver, the major site of hematopoiesis during embryonic development, acquires additional functions near birth. Among the important liver functions is the response to xenobiotic exposure due to expression of several cytochromes P450 (CYP) and drug efflux transporters. Expression of these genes is regulated by nuclear receptors such as the pregnane X receptor (PXR). In this study, regulation of xenobiotic responses during fetal liver development was analyzed using a fetal hepatocyte primary culture system derived from embryonic day 15 (E15) livers. Hepatocyte nuclear factor (HNF) 4α regulates the expression of many genes preferentially in the liver. Expression of several xenobiotic response genes as well as HNF4α was increased in fetal hepatocytes stimulated by the hepatic maturation factors oncostatin M (OSM) and Matrigel. To determine the contribution of HNF4α to xenobiotic responses in the fetal liver, fetal hepatocytes containing floxed HNF4α alleles were cultured and the HNF4α gene was inactivated by infection with an adenovirus containing the Cre gene. Expression of CYP3A11 and PXR was suppressed by inactivation of HNF4α. An HNF4α binding site was characterized in the PXR promoter and found to be required for activation of the PXR promoter in fetal hepatocytes. In conclusion, HNF4α is the key transcription factor regulating responses to xenobiotics through activation of the PXR gene during fetal liver development. References 1 Oliver IT, Martin RL, Fisher CJ, Yeoh GC. Enzymic differentiation in cultured foetal hepatocytes of the rat. Induction of serine dehydratase activity by dexamethasone and dibutyryl cyclic AMP. Differentiation 1983; 24: 234–238. 2 Perry ST, Rothrock R, Isham KR, Lee KL, Kenney FT. 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