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Individuals carrying an\n                  <jats:italic>APOE4<\/jats:italic>\n                  allele have an increased risk of AD and exhibit deficits in energy metabolism, including glucose utilization and mitochondrial dysfunction. While the role of APOE in the liver is well characterized, the impact of\n                  <jats:italic>APOE<\/jats:italic>\n                  genetic variation on hepatic health and metabolism remains poorly understood. We sought to investigate this using young female and male\n                  <jats:italic>APOE3<\/jats:italic>\n                  and\n                  <jats:italic>APOE4<\/jats:italic>\n                  targeted replacement mice. We also used\n                  <jats:italic>APOE<\/jats:italic>\n                  isogenic induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs) to examine specific effects in a human-relevant cell model. Proteomic and functional assays show that\n                  <jats:italic>APOE4<\/jats:italic>\n                  causes extensive changes to liver mitochondrial function in a sex-specific manner in mice and alters glucose and lipid metabolism.\n                  <jats:italic>APOE4<\/jats:italic>\n                  also impairs mitochondrial function in iHLCs and shifts metabolism towards glycolysis while modifying expression of extracellular matrix proteins. Additionally,\n                  <jats:italic>APOE4<\/jats:italic>\n                  iHLCs display a greater reliance on fatty acids as an energy source and show increased lipid accumulation. Taken together, our findings show that\n                  <jats:italic>APOE<\/jats:italic>\n                  genetic variation causes mitochondrial dysfunction and rewires hepatic metabolism.\n                <\/jats:p>","DOI":"10.1101\/2025.06.15.659815","type":"posted-content","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T12:00:16Z","timestamp":1750507216000},"source":"Crossref","is-referenced-by-count":5,"title":["<i>APOE4<\/i>\n                  drives widespread changes to the hepatic proteome and alters metabolic function"],"prefix":"10.64898","author":[{"given":"Colton R.","family":"Lysaker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea N.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Csikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edziu","family":"Franczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Benson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Thyfault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige C.","family":"Geiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Wilkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025070206161071000_2025.06.15.659815v1.1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006312"},{"key":"2025070206161071000_2025.06.15.659815v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"2025070206161071000_2025.06.15.659815v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2006.06.008"},{"key":"2025070206161071000_2025.06.15.659815v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705080114"},{"key":"2025070206161071000_2025.06.15.659815v1.5","doi-asserted-by":"crossref","unstructured":"Narasimhan S , Holtzman DM , Apostolova LG , Cruchaga C , Masters CL , Hardy J , et al. 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