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 ?-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.
The rationale for these studies is that understanding the mechanisms for the regulation of lipid metabolism in the nervous system will provide insight into basic neurochemistry and also for neurodegenerative diseases that have underlying metabolic complications. These studies will form the basis for understanding the contribution of lipids to neurological disease and enable the development of rational nutritional therapies.
|Frey, Julie L; Kim, Soohyun P; Li, Zhu et al. (2018) ?-Catenin Directs Long-Chain Fatty Acid Catabolism in the Osteoblasts of Male Mice. Endocrinology 159:272-284|
|Bowman, Caitlyn E; Wolfgang, Michael J (2018) Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism. Adv Biol Regul :|
|Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph et al. (2018) Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing. Mol Metab 7:45-56|
|Divakaruni, Ajit S; Hsieh, Wei Yuan; Minarrieta, Lucía et al. (2018) Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis. Cell Metab 28:490-503.e7|
|Yang, Haojun; Ralle, Martina; Wolfgang, Michael J et al. (2018) Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes. PLoS Biol 16:e2006519|
|Xiong, Jianhua; Kawagishi, Hiroyuki; Yan, Ye et al. (2018) A Metabolic Basis for Endothelial-to-Mesenchymal Transition. Mol Cell 69:689-698.e7|
|Kushwaha, Priyanka; Wolfgang, Michael J; Riddle, Ryan C (2018) Fatty acid metabolism by the osteoblast. Bone 115:8-14|
|Jernberg, Jennifer N; Bowman, Caitlyn E; Wolfgang, Michael J et al. (2017) Developmental regulation and localization of carnitine palmitoyltransferases (CPTs) in rat brain. J Neurochem 142:407-419|
|Kim, Soohyun P; Li, Zhu; Zoch, Meredith L et al. (2017) Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight 2:|
|Bowman, Caitlyn E; Rodriguez, Susana; Selen Alpergin, Ebru S et al. (2017) The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency. Cell Chem Biol 24:673-684.e4|
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