{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:51:41Z","timestamp":1787989901651,"version":"build-2784847793"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Constitutive androstane receptor (CAR) agonists, such as 1,4\u2010bis [2\u2010(3,5\u2010dichloropyridyloxy)] benzene (TCPOBOP), are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes without any associated liver injury. Yes\u2010associated protein (Yap) is a key transcription regulator that tightly controls organ size, including that of liver. Our and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP treatment in mice and the potential role of Yap in CAR\u2010driven proliferative response. Here, we investigated a direct role of Yap in CAR\u2010driven hepatomegaly and hepatocyte proliferation using hepatocyte\u2010specific Yap\u2010knockout (KO) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>Adeno\u2010associated virus 8\u2010thyroxine binding globulin promoter\u2010Cre recombinase vector was injected to Yap\u2010floxed mice for achieving hepatocyte\u2010specific Yap deletion followed by TCPOBOP treatment. Yap deletion did not decrease protein expression of CAR or CAR\u2010driven induction of drug metabolism genes (including cytochrome P450 [Cyp] 2b10, Cyp2c55, and UDP\u2010glucuronosyltransferase 1a1 [Ugt1a1]). However, Yap deletion substantially reduced TCPOBOP\u2010induced hepatocyte proliferation. TCPOBOP\u2010driven cell cycle activation was disrupted in Yap\u2010KO mice because of delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma protein. Furthermore, the induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2, and B1), and important mitotic regulators (such as Aurora B kinase and polo\u2010like kinase 1) was remarkably reduced in Yap\u2010KO mice. Microarray analysis revealed that 26% of TCPOBOP\u2010responsive genes that were mainly related to proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these proliferation genes through alerting expression of Myc and forkhead box protein M1, two critical transcriptional regulators of CAR\u2010mediated hepatocyte proliferation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study revealed an important role of Yap signaling in CAR\u2010driven hepatocyte proliferation; however, CAR\u2010driven induction of drug metabolism genes was independent of Yap.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31521","type":"journal-article","created":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T11:03:31Z","timestamp":1597403011000},"page":"2005-2022","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":21,"title":["Yes\u2010Associated Protein Is Crucial for Constitutive Androstane Receptor\u2010Driven Hepatocyte Proliferation But Not for Induction of Drug Metabolism Genes in Mice"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1716-9764","authenticated-orcid":false,"given":"Bharat","family":"Bhushan","sequence":"first","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Molina","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Koral","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Stoops","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4495-1054","authenticated-orcid":false,"given":"Wendy M.","family":"Mars","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Orr","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirish","family":"Paranjpe","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8437-3378","authenticated-orcid":false,"given":"Satdarshan P.","family":"Monga","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4190-188X","authenticated-orcid":false,"given":"Joseph","family":"Locker","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George K.","family":"Michalopoulos","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pittsburgh Liver Research Center,School of Medicine,University of Pittsburgh,Pittsburgh,PA,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"hep31521-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1134\/S0006297916040040","article-title":"Role of nuclear constitutive androstane receptor in regulation of hepatocyte proliferation and hepatocarcinogenesis","volume":"81","year":"2016","journal-title":"Biochemistry (Mosc)"},{"key":"hep31521-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1002\/hep.30109","article-title":"TCPOBOP\u2010induced hepatomegaly and hepatocyte proliferation are attenuated by combined disruption of MET and EGFR 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