Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
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DOI：
10.3390/cells8020182
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发表时间：
2019-02-01
期刊：
影响因子：
6
通讯作者：
Johnson, Lance A.
中科院分区：
文献类型：
--
作者：
Farmer, Brandon C.;Kluemper, Jude;Johnson, Lance A.
脂滴是一种富含能量的物质，与载脂蛋白E和神经退行性变有关。ApoE的E4等位基因(E4)是晚发性阿尔茨海默病(AD)发病的最强的遗传危险因素。由于E4携带者和AD患者都表现出脑脂代谢紊乱的状态，我们推测APOE可能在调节LD代谢中起作用。我们发现，与E3星形胶质细胞相比，表达E4的星形胶质细胞积累的LDs明显更多、更小。因此，Perilipin-2是一种重要的LD蛋白成分，在E4星形胶质细胞中的表达较高。然后，我们研究了脂肪酸(FA)的代谢，发现E4星形胶质细胞对棕榈酸的摄取减少，对外源供应的油酸和棕榈酸的氧化减少。然后我们测量了耗氧率，发现E4星形胶质细胞内源性FA氧化消耗了更多的氧气，并且由于不完全氧化积累了更多的LD衍生的代谢物。最后，我们发现E4星形胶质细胞对肉碱棕榈酰基转移酶-1的抑制比E3星形胶质细胞更敏感。这些发现为进一步研究星形胶质细胞脂肪储存、利用和神经退行性疾病之间的联系提供了可能性，这是APOE基因的作用。
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.