{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:13:19Z","timestamp":1783401199268,"version":"3.54.6"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Both iron overload and iron deficiency have been reported in obesity and metabolic syndromes. Due to the presence of multiple intracellular iron pools and the dynamic nature of iron mobilization and use, the actual status and contribution of free and metabolically active iron toward metabolic syndrome remain to be established. The discovery of nuclear receptor coactivator 4 (NCOA4) as a ferritinophagy receptor provides an opening to address the connection between iron and metabolic diseases. This study aims to specifically dissect the role of hepatic ferritinophagy in lipid metabolism and hepatic steatosis. We conducted a series of <jats:italic toggle=\"yes\">Ncoa4<\/jats:italic> gain\u2010 and loss\u2010of\u2010function experiments to examine how ferritinophagy affects lipid metabolism through phenotypic and lipidomic analyses both <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. We show that ferritinophagy is required to release iron from ferritin cages for biological use, and is induced by lipid loading <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and during the development of obesity <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. <jats:italic toggle=\"yes\">Ncoa4<\/jats:italic> knockdown impairs mitochondrial morphology and reduces palmitate\u2010induced lipid droplet formation in cultured cells and the development of hepatic steatosis in obese mice models. Importantly, the effect of <jats:italic toggle=\"yes\">Ncoa4<\/jats:italic> deficiency on mitochondrial morphology and lipid accumulation is specifically linked to lipidomic reductions in unsaturated fatty acid content in triglycerides and cardiolipins, and an external supply of unsaturated fatty acids reverses these phenotypes. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: This study shows that ferritinophagy\u2010derived iron supports fatty acid desaturation and the synthesis of unsaturated fatty acid\u2013rich lipids to reduce lipotoxicity. However, the continuous activation of ferritinophagy contributes to the development of hepatic steatosis and liver damage in obesity.<\/jats:p>","DOI":"10.1002\/hep4.2040","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T12:55:14Z","timestamp":1658408114000},"page":"2640-2653","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["Co\u2010regulation of hepatic steatosis by ferritinophagy and unsaturated fatty acid supply"],"prefix":"10.1097","volume":"6","author":[{"given":"Ning","family":"Li","sequence":"first","affiliation":[{"name":"School of Life Sciences,Tsinghua University,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilie","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Life Sciences,Tsinghua University,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haipeng","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Life Sciences,Tsinghua University,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suneng","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Basic Research,Guangzhou Laboratory,Guangdong,China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"hep42040-bib-0001-20241127","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev.physiol.69.031905.164337","article-title":"Iron homeostasis","volume":"69","year":"2007","journal-title":"Annu Rev Physiol"},{"key":"hep42040-bib-0002-20241127","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s13238-014-0083-7","article-title":"Essential functions of iron\u2010requiring proteins in DNA replication, 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