<i>APOE4</i> drives widespread changes to the hepatic proteome and alters metabolic function

Apolipoprotein E (APOE) is essential for lipid homeostasis and has been extensively studied in Alzheimer's disease (AD). Individuals carrying an <i>APOE4</i> 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 <i>APOE</i> genotype on hepatic health and metabolism remains poorly understood. We sought to investigate this using young <i>APOE3</i> and <i>APOE4</i>-targeted replacement mice and isogenic-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs). Proteomic and functional assays show that <i>APOE</i>4 causes extensive changes to liver mitochondrial function in a sex-specific manner in mice and alters glucose and lipid metabolism. <i>APOE</i>4 also impairs mitochondrial function in iHLCs, shifts metabolism towards glycolysis, increases reliance on fatty acid utilization, and drives lipid accumulation. Together, these findings show that <i>APOE</i> genetic variation causes mitochondrial dysfunction and rewires hepatic metabolism.