Regulation of Neuronal Lipid Homeostasis By Thioesterases

 描述（由申请人提供）：神经元对脂质具有独特的作用，与其他细胞类型不同，并配备有调节细胞内脂质代谢的专门机制。尽管广泛认识到神经元的脂质组成对于人类发育至关重要，并且脂质代谢的缺陷导致严重的和使人衰弱的神经系统疾病，但是缺乏关于神经元如何在基本水平上调节细胞内脂质代谢的理解。使用组织特异性转基因和基因敲除小鼠模型，我们发现神经元通过将长链酰基辅酶A水解为游离脂肪酸和辅酶A来调节脂肪酸通量并防止脂毒性。这是由神经元特异性酰基辅酶A硫酯酶7（ACOT 7）介导的。小鼠和人类中ACOT 7的缺失导致行为缺陷和神经退行性疾病。我们开发了一个新的模型，描述了神经系统内神经元和星形胶质细胞之间的脂肪酸协调代谢。我们假设这是由神经元内的酰基辅酶A水解和星形胶质细胞内的脂肪酸β-氧化介导的。由于脂肪酸对大脑功能和病理生理学的至关重要性，因此非常需要对神经系统中的脂肪酸代谢进行更深入的了解。本文描述的研究将详细说明这些基本的未回答的问题。为了验证这些假设，我们提出了两个具体的目标：1）确定ACOT 7的神经保护作用和调节。2)确定脑脂肪酸氧化的作用和要求。本项目的长期目标是阐明 神经系统用来调节脂肪酸代谢的分子机制。我们的期望是，我们提出的研究将描述脂肪酸代谢如何在神经系统中调节的新机制，更广泛地说，促进我们对脂质稳态在神经系统疾病中的作用的理解。

 DESCRIPTION (provided by applicant): Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipid metabolism. Although it is widely appreciated that the lipid composition of neurons is criticl for human development and defects in lipid metabolism result in severe and debilitating neurological disease, there is a dearth of understanding about how neurons regulate intracellular lipid metabolism at a fundamental level. Using tissue specific transgenic and knockout mouse models we have discovered that neurons regulate fatty acid flux and prevent lipotoxicity by hydrolyzing long chain acyl-CoAs to free fatty acid and CoA. This is mediated by the neuron-specific Acyl-CoA Thioesterase 7 (ACOT7). The loss of ACOT7 in mice and humans results in behavioral deficits and neurodegenerative disease. We have developed a new model describing the coordinated metabolism of fatty acids within the nervous system between neurons and astrocytes. We hypothesize that this is mediated by acyl-CoA hydrolysis within the neuron and fatty acid β-oxidation within the astrocyte. Because of the critical importance of fatt acids to brain function and pathophysiology, a deeper understanding of fatty acid metabolism in the nervous system is greatly needed. The studies described herein will detail these fundamental unanswered questions. To test these hypotheses we propose two specific aims: 1) Determine the neuroprotective role and regulation of ACOT7. 2) Determine the roles and requirements for brain fatty acid oxidation. The long-term goal of this project is to elucidate the molecular mechanisms employed by the nervous system to regulate the metabolism of fatty acids. The expectation is that our proposed studies will describe new mechanisms for how fatty acid metabolism is regulated in the nervous system and more broadly, advance our understanding of the role of lipid homeostasis in neurological disease.