{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:50Z","timestamp":1760143250992,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Frankfurter Forschungsf\u00f6rderung"},{"name":"German Research Foundation (DFG)"},{"name":"German Federal Ministry of Education and Research (BMBF)"},{"name":"Hessian Ministry of Higher Education, Research and the Arts (HMWK)"},{"name":"European Union\u2019s Horizon 2020 research and innovation program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1\u03b1) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1\u03b1 in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1\u03b1 expression and the intracellular pathway of HIF-1\u03b1 induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1\u03b1 expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1\u03b1 in human liver tissue. Intrahepatic HIF-1\u03b1 expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1\u03b1 was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1\u03b1 expression was not elevated. In human liver tissue samples, HIF-1\u03b1 expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1\u03b1 expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.<\/jats:p>","DOI":"10.3390\/ijms25031542","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T08:56:01Z","timestamp":1706259361000},"page":"1542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8475-8369","authenticated-orcid":false,"given":"Marcus M.","family":"M\u00fccke","sequence":"first","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nihad","family":"El Bali","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina M.","family":"Schwarzkopf","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank Erhard","family":"Uschner","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"Department of Internal Medicine B, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5162-1048","authenticated-orcid":false,"given":"Nico","family":"Kraus","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larissa","family":"Eberle","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria Therese","family":"M\u00fccke","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Bein","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Beyer","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Wild","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2195-3666","authenticated-orcid":false,"given":"Robert","family":"Schierwagen","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"Department of Internal Medicine B, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Klein","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"Department of Internal Medicine B, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Zeuzem","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Welsch","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"Department of Internal Medicine B, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1089-9710","authenticated-orcid":false,"given":"Angela","family":"Brieger","sequence":"additional","affiliation":[{"name":"Medical Clinic 1, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1053\/j.gastro.2013.02.042","article-title":"Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis","volume":"144","author":"Moreau","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jhep.2016.10.012","article-title":"Diagnosis and prognosis of acute on chronic liver failure (ACLF) in 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