Cholesterol Biosynthesis and Uptake in Developing Neurons
Cholesterol Biosynthesis and Uptake in Developing Neurons
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DOI：
10.1021/acschemneuro.9b00248
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Mirnics, Karoly
中科院分区：
文献类型：
--
作者：
Genaro-Mattos, Thiago C.;Anderson, Allison;Mirnics, Karoly
脑胆固醇生物合成是一个独立的、不同于全身胆固醇稳态的过程，始于胚胎发育。为了更好地了解神经元和神经胶质对脑胆固醇库的贡献，我们在对照、Dhcr7（-/-）和Dhcr24（-/-）细胞培养中研究了这一过程。我们的LC-MS/MS方法允许我们在神经元分化过程中测量几种不同的甾醇中间体和胆固醇。我们发现发育中的皮质神经元依赖于内源性胆固醇合成，并利用来自周围环境的apoe复合物胆固醇和固醇前体。发育中的神经元和星形胶质细胞都将胆固醇释放到它们所在的环境中。我们的研究还发现，与星形胶质细胞相比，发育中的神经元每个细胞产生的胆固醇量明显更高。最后，我们确定神经元和星形胶质细胞都优先使用布洛赫甾醇生物合成途径，其中去氨甾醇是胆固醇的直接前体。总的来说，我们的研究表明，在大脑发育过程中，神经元的内源性固醇合成是一个关键的、复杂的内稳态调节过程。
Brain cholesterol biosynthesis, a separate and distinct process from whole-body cholesterol homeostasis, starts during embryonic development. To gain a better understanding of the neuronal and glial contributions to the brain cholesterol pool, we studied this process in control, Dhcr7(-/-), and Dhcr24(-/-) cell cultures. Our LC-MS/MS method allowed us to measure several different sterol intermediates and cholesterol during neuronal differentiation. We found that developing cortical neurons rely on endogenous cholesterol synthesis and utilize ApoE-complexed cholesterol and sterol precursors from their surroundings. Both developing neurons and astrocytes release cholesterol into their local environment. Our studies also uncovered that developing neurons produced significantly higher amounts of cholesterol per cell than the astrocytes. Finally, we established that both neurons and astroglia preferentially use the Bloch sterol biosynthesis pathway, where desmosterol is the immediate precursor to cholesterol. Overall, our studies suggest that endogenous sterol synthesis in developing neurons is a critical and complexly regulated homeostatic process during brain development.