Dietary intake of excess fat or carbohydrate results in increased synthesis and storage of triacylglycerol (TAG). The long-chain fatty acids (FA) that contribute to TAG synthesis must be first converted to acyl-CoAs by long-chain acyl-CoA synthetase (ACSL). Because acyl-CoAs lie at a branch-point of storage and mitochondrial ?-oxidation, the fate of the acyl-CoAs formed may contribute to, or counteract, nutritional disorders related to increased TAG storage like obesity, fatty liver, atherosclerosis, and diabetes. We hypothesize that 1) ACSL1 is able to direct FA towards ?-oxidation in highly oxidative tissues because the enzyme interacts with carnitine acyltranferase to hand off its acyl-CoA product;2) that the function of ACSL1 differs in liver because at least 50% of the protein is present on the endoplasmic reticulum where it interacts with glycerolipid acyltransferases;and 3) that the mechanism for these differences lies both in the membrane association and phosphorylation status of ACSL1. Further, we propose that tissue use of glucose rather than FA as a fuel source is not without cost, and that the metabolic and functional problems arising from this use may be dangerous for organ function and insulin signaling. We further hypothesize, in keeping with the proposition that each ACSL directs FA towards a specific fate, that the ACSL4 isoform functions to regulate the entry of arachidonate into pathways of phospholipid synthesis versus eicosanoid formation. Our studies will address critical gaps in our knowledge about the metabolic fates of FA as substrates for complex lipid formation, as metabolic fuels, as precursors for eicosanoid signaling, as regulators of insulin action, and as transcription factor ligands.
This project will enhance our understanding of insulin resistance, the metabolic syndrome, and cardiac and skeletal muscle fuel metabolism by determining the functions of two of the long-chain acyl-CoA synthetase isoforms in different tissues, by examining how they direct fatty acids towards different downstream pathways, and by investigating how abnormalities in ACSL function alters insulin signaling in cardiac and skeletal muscle.
|Young, Pamela A; Senkal, Can E; Suchanek, Amanda L et al. (2018) Long-chain acyl-CoA synthetase 1 interacts with key proteins that activate and direct fatty acids into niche hepatic pathways. J Biol Chem 293:16724-16740|
|Killion, Elizabeth A; Reeves, Andrew R; El Azzouny, Mahmoud A et al. (2018) A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Mol Metab 9:43-56|
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|Klett, Eric L; Chen, Shufen; Yechoor, Alekhya et al. (2017) Long-chain acyl-CoA synthetase isoforms differ in preferences for eicosanoid species and long-chain fatty acids. J Lipid Res 58:884-894|
|Alves-Bezerra, Michele; Klett, Eric L; De Paula, Iron F et al. (2016) Long-chain acyl-CoA synthetase 2 knockdown leads to decreased fatty acid oxidation in fat body and reduced reproductive capacity in the insect Rhodnius prolixus. Biochim Biophys Acta 1861:650-62|
|Pascual, Florencia; Coleman, Rosalind A (2016) Fuel availability and fate in cardiac metabolism: A tale of two substrates. Biochim Biophys Acta 1861:1425-33|
|Grevengoed, Trisha J; Cooper, Daniel E; Young, Pamela A et al. (2015) Loss of long-chain acyl-CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation. FASEB J 29:4641-53|
|Cooper, Daniel E; Young, Pamela A; Klett, Eric L et al. (2015) Physiological Consequences of Compartmentalized Acyl-CoA Metabolism. J Biol Chem 290:20023-31|
|Schisler, Jonathan C; Grevengoed, Trisha J; Pascual, Florencia et al. (2015) Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin. J Am Heart Assoc 4:|
|Li, Lei O; Grevengoed, Trisha J; Paul, David S et al. (2015) Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. Diabetes 64:23-35|
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