APOE4 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 APOE4 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 APOE genotype on hepatic health and metabolism remains poorly understood. We sought to investigate this using young APOE3 and APOE4-targeted replacement mice and isogenic-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs). Proteomic and functional assays show that APOE4 causes extensive changes to liver mitochondrial function in a sex-specific manner in mice and alters glucose and lipid metabolism. APOE4 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 APOE genetic variation causes mitochondrial dysfunction and rewires hepatic metabolism.