{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:15:37Z","timestamp":1785150937292,"version":"3.55.0"},"reference-count":81,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["DK134581"],"award-info":[{"award-number":["DK134581"]}]},{"name":"NIH","award":["DK133406"],"award-info":[{"award-number":["DK133406"]}]},{"name":"NIH","award":["DK130949"],"award-info":[{"award-number":["DK130949"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The activation of hypoxia-inducible factors (HIF)-1\u03b1 and 2\u03b1 in the liver is closely linked to the progression of fatty liver diseases. Prior studies indicated that disrupting hepatocyte HIF-2\u03b1 attenuates diet-induced hepatic steatosis, subsequently decreasing fibrosis. However, the direct role of hepatocyte HIF-2\u03b1 in liver fibrosis has not been addressed. Hepatic HIF-2\u03b1 expression was examined in mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. Conditional hepatocyte Hif-2\u03b1 knockout mice were employed to investigate the role of hepatocyte HIF-2\u03b1 in fibrosis. Markers of apoptosis, proliferation, inflammation, and fibrosis were assessed through biochemical, molecular, and histological analyses. We found an induction of HIF-2\u03b1 in CCL4-injected liver injury and fibrosis mouse models. Hepatocyte-specific deletion of HIF-2\u03b1 attenuated stellate cell activation and fibrosis, with no significant difference in inflammation. Disrupting hepatocyte HIF-2\u03b1 led to reduced injury-mediated hepatocellular apoptosis. Surviving hepatocytes exhibited hypertrophy, which was strongly associated with the activation of c-JUN signaling. Our study demonstrates a direct role of hepatocyte HIF-2\u03b1 in liver fibrosis by promoting hepatocyte apoptosis. The reduction in apoptosis and induction of hepatocyte hypertrophy following HIF-2\u03b1 disruption is closely linked to enhanced c-JUN signaling, a survival mechanism in response to liver injury. These findings highlight HIF-2\u03b1 as a potential therapeutic target for liver fibrosis.<\/jats:p>","DOI":"10.3390\/ijms252313114","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T03:44:47Z","timestamp":1733456687000},"page":"13114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Hypoxia-Inducible Factor-2\u03b1 Promotes Liver Fibrosis by Inducing Hepatocellular Death"],"prefix":"10.3390","volume":"25","author":[{"given":"Raja Gopal Reddy","family":"Mooli","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanunjay","family":"Mukhi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-2717","authenticated-orcid":false,"given":"Mikayla","family":"Watt","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerababu","family":"Nagati","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Reed","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9363-310X","authenticated-orcid":false,"given":"Nikita K.","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Oertel","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadeesh K.","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/hep.25670","article-title":"Fibrosis-dependent mechanisms of hepatocarcinogenesis","volume":"56","author":"Zhang","year":"2012","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. 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