Apolipoprotein E (APOE) plays an important role in human cells by transporting and metabolizing lipids and assisting energy generation. A variant in the gene encoding APOE, APOE4, increases the risk of Alzheimer’s disease, but how it does this is not well understood.
Here, it was reported, 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. The authors combined lipidomics and 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. The authors then identified the genetic and chemical modulators of this lipid disruption. The study shows 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. The study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. It is possible that manipulation of lipid metabolism may be a therapeutic approach to alleviate the consequences of carrying the APOE4 allele.
APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
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