{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:00:20Z","timestamp":1792036820912,"version":"4.4.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T00:00:00Z","timestamp":1716940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK98414"],"award-info":[{"award-number":["R01DK98414"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nuclear receptors such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor-alpha (PPAR\u03b1), and transcription factors with nuclear receptor type activity such as aryl hydrocarbon receptor (AhR) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4\u03b1) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4\u03b1 is essential for the function of these 4 major xenosensors. Wild-type (WT) and hepatocyte-specific Hnf4a null (HNF4\u03b1-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30\u2009\u00b5g\/kg), CAR (TCPOBOP, 2.5\u2009\u00b5g\/g), PXR, (PCN, 100\u2009\u00b5g\/g), and PPAR\u03b1 (WY-14643, 1\u2009mg\/kg). Blood and liver tissue samples were collected to study receptor activation. TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW\/BW) in either WT or HNF4\u03b1-KO mice. Further, TCDD activated AhR in both WT and HNF4\u03b1-KO mice, confirmed by increase in expression of AhR target genes. TCPOBOP (CAR agonist) significantly increased the LW\/BW ratio and CAR target gene expression in WT mice, but not in HNF4\u03b1-KO mice. PCN (a mouse PXR agonist) significantly increased LW\/BW ratio in both WT and HNF4\u03b1-KO mice however, failed to induce PXR target genes in HNF4\u03b1-KO mice. The treatment of WY-14643 (PPAR\u03b1 agonist) increased LW\/BW ratio and PPAR\u03b1 target gene expression in WT mice but not in HNF4\u03b1-KO mice. Together, these data indicate that the function of CAR, PXR, and PPAR\u03b1 but not of AhR was disrupted in HNF4\u03b1-KO mice. These results demonstrate that HNF4\u03b1 function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae069","type":"journal-article","created":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T17:10:58Z","timestamp":1716916258000},"page":"346-356","source":"Crossref","is-referenced-by-count":8,"title":["Regulation of hepatic xenosensor function by HNF4alpha"],"prefix":"10.1093","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3277-5463","authenticated-orcid":false,"given":"Manasi","family":"Kotulkar","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9047-9497","authenticated-orcid":false,"given":"Diego","family":"Paine-Cabrera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-3112","authenticated-orcid":false,"given":"Dakota R","family":"Robarts","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6741-7164","authenticated-orcid":false,"given":"Udayan","family":"Apte","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center , Kansas City, KS 66160, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,29]]},"reference":[{"issue":"5","key":"2024072915004712000_kfae069-B1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2133\/dmpk.22.391","article-title":"Hepatocyte nuclear factor 1 alpha and 4 alpha are factors involved in interindividual variability in the expression of UGT1A6 and UGT1A9 but not UGT1A1, UGT1A3 and UGT1A4 mRNA in human livers","volume":"22","author":"Aueviriyavit","year":"2007","journal-title":"Drug Metab Pharmacokinet"},{"issue":"10","key":"2024072915004712000_kfae069-B2","doi-asserted-by":"crossref","first-page":"7345","DOI":"10.1074\/jbc.M111.334599","article-title":"Suppression of hepatocyte proliferation by hepatocyte nuclear factor 4alpha in adult mice","volume":"287","author":"Bonzo","year":"2012","journal-title":"J Biol Chem"},{"issue":"3","key":"2024072915004712000_kfae069-B3","doi-asserted-by":"crossref","first-page":"G283","DOI":"10.1152\/ajpgi.00205.2016","article-title":"Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells","volume":"312","author":"Brocker","year":"2017","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"20","key":"2024072915004712000_kfae069-B4","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1101\/gad.8.20.2466","article-title":"Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos","volume":"8","author":"Chen","year":"1994","journal-title":"Genes Dev"},{"issue":"4","key":"2024072915004712000_kfae069-B5","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1002\/hep.22129","article-title":"Pregnane X receptor is essential for normal progression of liver regeneration","volume":"47","author":"Dai","year":"2008","journal-title":"Hepatology"},{"issue":"36","key":"2024072915004712000_kfae069-B6","doi-asserted-by":"crossref","first-page":"26540","DOI":"10.1074\/jbc.M600931200","article-title":"Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha","volume":"281","author":"Ding","year":"2006","journal-title":"J Biol Chem"},{"issue":"44","key":"2024072915004712000_kfae069-B7","doi-asserted-by":"crossref","first-page":"18831","DOI":"10.1073\/pnas.0909731106","article-title":"Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease","volume":"106","author":"Dong","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024072915004712000_kfae069-B8","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0076-6879(05)00028-5","article-title":"Coordinate transcriptional regulation of transport and metabolism","volume":"400","author":"Eloranta","year":"2005","journal-title":"Methods Enzymol"},{"issue":"9","key":"2024072915004712000_kfae069-B9","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.it.2009.06.005","article-title":"The aryl hydrocarbon receptor in immunity","volume":"30","author":"Esser","year":"2009","journal-title":"Trends Immunol"},{"issue":"1","key":"2024072915004712000_kfae069-B10","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2133\/dmpk.23.2","article-title":"Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription","volume":"23","author":"Gonzalez","year":"2008","journal-title":"Drug Metab Pharmacokinet"},{"issue":"2","key":"2024072915004712000_kfae069-B11","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/hep.32326","article-title":"Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans","volume":"76","author":"Gunewardena","year":"2022","journal-title":"Hepatology"},{"key":"2024072915004712000_kfae069-B12","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/bcpt.13004","article-title":"Cytochrome P450 induction and xeno-sensing receptors pregnane x receptor, constitutive androstane receptor, aryl hydrocarbon receptor and peroxisome proliferator-activated receptor alpha at the crossroads of toxicokinetics and toxicodynamics","volume":"123(Suppl 5)","author":"Hakkola","year":"2018","journal-title":"Basic Clin Pharmacol Toxicol"},{"issue":"4","key":"2024072915004712000_kfae069-B13","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1128\/MCB.21.4.1393-1403.2001","article-title":"Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis","volume":"21","author":"Hayhurst","year":"2001","journal-title":"Mol Cell Biol"},{"issue":"6","key":"2024072915004712000_kfae069-B14","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1210\/me.2004-0520","article-title":"Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor","volume":"19","author":"Huang","year":"2005","journal-title":"Mol Endocrinol"},{"issue":"2","key":"2024072915004712000_kfae069-B15","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1002\/hep.30405","article-title":"Hepatocyte nuclear factor 4 alpha activation is essential for termination of liver regeneration in mice","volume":"70","author":"Huck","year":"2019","journal-title":"Hepatology"},{"issue":"6","key":"2024072915004712000_kfae069-B16","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.coph.2010.08.010","article-title":"HNF4alpha\u2014role in drug metabolism and potential drug target?","volume":"10","author":"Hwang-Verslues","year":"2010","journal-title":"Curr Opin Pharmacol"},{"issue":"28","key":"2024072915004712000_kfae069-B17","doi-asserted-by":"crossref","first-page":"25257","DOI":"10.1074\/jbc.M203126200","article-title":"Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4alpha (HNF4alpha). HNF4alpha regulates ornithine transcarbamylase in vivo","volume":"277","author":"Inoue","year":"2002","journal-title":"J Biol Chem"},{"issue":"4","key":"2024072915004712000_kfae069-B18","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1007\/s00109-005-0013-5","article-title":"Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression","volume":"84","author":"Inoue","year":"2006","journal-title":"J Mol Med (Berl)"},{"issue":"4","key":"2024072915004712000_kfae069-B19","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1074\/jbc.M311015200","article-title":"Hepatocyte nuclear factor 4alpha is a central regulator of bile acid conjugation","volume":"279","author":"Inoue","year":"2004","journal-title":"J Biol Chem"},{"issue":"1","key":"2024072915004712000_kfae069-B20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/hep.30131","article-title":"Pregnane X receptor regulates liver size and liver cell fate by yes-associated protein activation in mice","volume":"69","author":"Jiang","year":"2019","journal-title":"Hepatology"},{"issue":"3","key":"2024072915004712000_kfae069-B21","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1053\/jhep.2001.22176","article-title":"Cytochrome p450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus-mediated antisense targeting","volume":"33","author":"Jover","year":"2001","journal-title":"Hepatology"},{"issue":"5","key":"2024072915004712000_kfae069-B22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.2174\/138920009788898000","article-title":"Transcriptional regulation of cytochrome P450 genes by the nuclear receptor hepatocyte nuclear factor 4-alpha","volume":"10","author":"Jover","year":"2009","journal-title":"Curr Drug Metab"},{"issue":"6","key":"2024072915004712000_kfae069-B23","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1053\/jhep.2003.50212","article-title":"Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development","volume":"37","author":"Kamiya","year":"2003","journal-title":"Hepatology"},{"issue":"6","key":"2024072915004712000_kfae069-B24","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1124\/dmd.106.009365","article-title":"Involvement of hepatocyte nuclear factor 4alpha in the different expression level between CYP2C9 and CYP2C19 in the human liver","volume":"34","author":"Kawashima","year":"2006","journal-title":"Drug Metab Dispos"},{"issue":"4","key":"2024072915004712000_kfae069-B25","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1097\/HEP.0000000000000367","article-title":"Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury","volume":"78","author":"Kotulkar","year":"2023","journal-title":"Hepatology"},{"issue":"4","key":"2024072915004712000_kfae069-B26","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta c(t)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"issue":"9","key":"2024072915004712000_kfae069-B27","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1124\/dmd.118.081042","article-title":"The roles of xenobiotic receptors: beyond chemical disposition","volume":"46","author":"Mackowiak","year":"2018","journal-title":"Drug Metab Dispos"},{"issue":"3","key":"2024072915004712000_kfae069-B28","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1128\/MCB.00927-09","article-title":"Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism","volume":"30","author":"Martinez-Jimenez","year":"2010","journal-title":"Mol Cell Biol"},{"issue":"4","key":"2024072915004712000_kfae069-B29","first-page":"263","article-title":"Basic review of the cytochrome P450 system","volume":"4","author":"McDonnell","year":"2013","journal-title":"J Adv Pract Oncol"},{"key":"2024072915004712000_kfae069-B30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.pharmtox.47.120505.105349","article-title":"The tangle of nuclear receptors that controls xenobiotic metabolism and transport: Crosstalk and consequences","volume":"48","author":"Pascussi","year":"2008","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"5","key":"2024072915004712000_kfae069-B31","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.jcmgh.2022.01.014","article-title":"Regulation of liver regeneration by hepatocyte O-GlcNAcylation in mice","volume":"13","author":"Robarts","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"12B","key":"2024072915004712000_kfae069-B32","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1101\/gad.4.12b.2353","article-title":"Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily","volume":"4","author":"Sladek","year":"1990","journal-title":"Genes Dev"},{"issue":"3","key":"2024072915004712000_kfae069-B33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.steroids.2006.12.006","article-title":"CAR and PXR: the xenobiotic-sensing receptors","volume":"72","author":"Timsit","year":"2007","journal-title":"Steroids"},{"issue":"3","key":"2024072915004712000_kfae069-B34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3727\/105221615X14181438356292","article-title":"Role of hepatocyte nuclear factor 4alpha (HNF4alpha) in cell proliferation and cancer","volume":"16","author":"Walesky","year":"2015","journal-title":"Gene Expr"},{"issue":"6","key":"2024072915004712000_kfae069-B35","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1002\/hep.26251","article-title":"Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents","volume":"57","author":"Walesky","year":"2013","journal-title":"Hepatology"},{"issue":"1","key":"2024072915004712000_kfae069-B36","doi-asserted-by":"crossref","first-page":"G26","DOI":"10.1152\/ajpgi.00064.2012","article-title":"Hepatocyte-specific deletion of hepatocyte nuclear factor-4alpha in adult mice results in increased hepatocyte proliferation","volume":"304","author":"Walesky","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"2","key":"2024072915004712000_kfae069-B37","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/toxsci\/kfm104","article-title":"WY-14,643 induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase","volume":"98","author":"Woods","year":"2007","journal-title":"Toxicol Sci"},{"issue":"3","key":"2024072915004712000_kfae069-B38","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF02977789","article-title":"Induction of phase I, II and III drug metabolism\/transport by xenobiotics","volume":"28","author":"Xu","year":"2005","journal-title":"Arch Pharm Res"},{"issue":"5","key":"2024072915004712000_kfae069-B39","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1111\/cpr.12282","article-title":"Role of AhR in positive regulation of cell proliferation and survival","volume":"49","author":"Yin","year":"2016","journal-title":"Cell Prolif"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfae069\/58179521\/kfae069.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/200\/2\/346\/58666360\/kfae069.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/200\/2\/346\/58666360\/kfae069.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T19:25:56Z","timestamp":1722281156000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/200\/2\/346\/7684956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,29]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,5,29]]},"published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfae069","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.11.561888","asserted-by":"object"}]},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,5,29]]}}}