Lipid droplets (LDs) serve as energy rich reservoirs and have been associated with apolipoprotein E (APOE) and neurodegeneration. The E4 allele of APOE (E4) is the strongest genetic risk factor for the development of late onset Alzheimer’s disease (AD). Since both E4 carriers and individuals with AD exhibit a state of cerebral lipid dyshomeostasis, we hypothesized that APOE may play a role in regulating LD metabolism. We found that astrocytes expressing E4 accumulate significantly more and smaller LDs compared to E3 astrocytes. Accordingly, expression of perilipin-2, an essential LD protein component, was higher in E4 astrocytes. We then probed fatty acid (FA) metabolism and found E4 astrocytes to exhibit decreased uptake of palmitate, and decreased oxidation of exogenously supplied oleate and palmitate. We then measured oxygen consumption rate, and found E4 astrocytes to consume more oxygen for endogenous FA oxidation and accumulate more LD-derived metabolites due to incomplete oxidation. Lastly, we found that E4 astrocytes are more sensitive to carnitine palmitoyltransferase-1 inhibition than E3 astrocytes. These findings offer the potential for further studies investigating the link between astrocyte lipid storage, utilization, and neurodegenerative disease as a function of APOE genotype.
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This research was funded by the American Heart Association, grant number 19PRE34380094, B.C.F.; National Institute on Aging 1R01AG060056-01, L.A.J.; NIH COBRE P20 GM103527, L.J.
The following are available online at https://www.mdpi.com/2073-4409/8/2/182/s1, Figure S1: E4 astrocytes express more perilipin-2, Figure S2: E4 astrocytes secrete less ApoE into the media and have less intracellular ApoE, Figure S3: E4 astrocytes form more lipid droplets.
Farmer, Brandon C.; Kluemper, Jude; and Johnson, Lance A., "Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation" (2019). Physiology Faculty Publications. 142.