{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:54:10Z","timestamp":1790992450177,"version":"4.1.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Hepatocyte nuclear factor 4 alpha (HNF4\u03b1) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4\u03b1 activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We developed an HNF4\u03b1 target gene signature, which can accurately determine HNF4\u03b1 activity, and performed an exhaustive <jats:italic toggle=\"yes\">in silico<\/jats:italic> analysis using hierarchical and K\u2010means clustering, survival, and rank\u2010order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4\u03b1 activity to CLD progression of various etiologies, including HCV\u2010 and HBV\u2010induced liver cirrhosis (LC), NAFLD\/NASH, and HCC, was determined. Results revealed a step\u2010wise reduction in HNF4\u03b1 activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4\u03b1 signature showed that loss of HNF4\u03b1 activity was associated with progression of Child\u2010Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4\u03b1 activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4\u03b1 activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, these data indicate that loss of HNF4\u03b1 function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32326","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T10:38:44Z","timestamp":1641811124000},"page":"372-386","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":59,"title":["Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans"],"prefix":"10.1097","volume":"76","author":[{"given":"Sumedha","family":"Gunewardena","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Huck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Walesky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-3112","authenticated-orcid":false,"given":"Dakota","family":"Robarts","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Weinman","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Kansas Medical Center,Kansas City,Kansas,USA"}],"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,Kansas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"hep32326-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2133\/dmpk.23.2","article-title":"Regulation of hepatocyte nuclear factor 4 alpha\u2010mediated 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