Intracellular long chain fatty acyl-CoAs provide the substrate for acylation reactions for membrane phospholipid biosynthesis, protein palmitoylation and cellular oxidative energy among others. Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipids. Although it is widely appreciated that the lipid composition of neurons is critical 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. We have found that neuronal-specific acyl-CoA thioesterases are critical for neuronal development and function. We hypothesize that acyl-CoA thioesterase 7 (ACOT7) functions at an essential regulatory step for fatty acid utilization in neurons and that dysregulation of ACOT7 results in neurological dysfunction. To test this hypothesis we propose three specific aims: 1) Determine the role of ACOT7 in regulating cellular lipid metabolism. 2) Determine the neuron-specific role of ACOT7 in lipid metabolism and 3) Determine the role of ACOT7 in neurological pathophysiology.
The rationale for these studies is that understanding the mechanisms for neuron-specific regulation of lipid metabolism will provide insight into the role of lipids in normal neurophysiology and development, and also for neurodegenerative diseases such as ALS, Parkinson's, and Alzheimer's disease which have been shown to have underlying metabolic complications. These studies will form the basis for understanding the contribution of lipids to neurological disease and enable the development of targeted therapies.
|Kushwaha, Priyanka; Wolfgang, Michael J; Riddle, Ryan C (2017) Fatty acid metabolism by the osteoblast. Bone :|
|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:|
|Kim, Soohyun P; Frey, Julie L; Li, Zhu et al. (2017) Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci U S A 114:E11238-E11247|
|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|
|Wall, Valerie Z; Barnhart, Shelley; Kramer, Farah et al. (2017) Inflammatory stimuli induce acyl-CoA thioesterase 7 and remodeling of phospholipids containing unsaturated long (?C20)-acyl chains in macrophages. J Lipid Res 58:1174-1185|
|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|
|Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S et al. (2017) Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance. Cell Rep 20:655-667|
|Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph et al. (2017) Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction. Am J Physiol Endocrinol Metab 312:E381-E393|
|Lee, Jieun; Choi, Joseph; Scafidi, Susanna et al. (2016) Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation. Cell Rep 16:201-212|
|Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan et al. (2016) The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria. J Biol Chem 291:16644-58|
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