LAUSR

APOE4-disrupted intracellular lipid homeostasis in human and yeast cells was reversed by promoting phospholipid synthesis through choline supplementation. APOE4 disrupts lipid homeostasis in glia APOE4 is a strong genetic risk factor for many diseases, most notably, late-onset Alzheimer’s disease. Sienski et al. now show that cultured human glia with an APOE4 genotype accumulated unsaturated triglycerides leading to a lipid imbalance. Using genetic screens in yeast, the authors discovered that promoting phospholipid synthesis through choline supplementation of culture medium restored a normal lipid state in APOE4-expressing yeast cells. The authors then demonstrated that choline supplementation also restored lipid homeostasis in human APOE4 astrocytes. These findings suggest that modulating glial metabolism could help to reduce APOE4-associated disease risk. The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4. Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele.