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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Pawlyk, Aaron
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Public Health
Chapel Hill
United States
Zip Code
Grevengoed, Trisha J; Klett, Eric L; Coleman, Rosalind A (2014) Acyl-CoA metabolism and partitioning. Annu Rev Nutr 34:1-30
Paul, David S; Grevengoed, Trisha J; Pascual, Florencia et al. (2014) Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin. Biochim Biophys Acta 1841:880-7
Modi, Hiren R; Basselin, Mireille; Taha, Ameer Y et al. (2013) Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder. Biochim Biophys Acta 1831:880-6
Li, Xin; Gonzalez, Oscar; Shen, Xia et al. (2013) Endothelial acyl-CoA synthetase 1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment. Arterioscler Thromb Vasc Biol 33:232-40
Teng, Ya-Wen; Ellis, Jessica M; Coleman, Rosalind A et al. (2012) Mouse betaine-homocysteine S-methyltransferase deficiency reduces body fat via increasing energy expenditure and impairing lipid synthesis and enhancing glucose oxidation in white adipose tissue. J Biol Chem 287:16187-98
Kanter, Jenny E; Kramer, Farah; Barnhart, Shelley et al. (2012) Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc Natl Acad Sci U S A 109:E715-24
Coleman, Rosalind A; Mashek, Douglas G (2011) Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling. Chem Rev 111:6359-86
Shimshoni, Jakob A; Basselin, Mireille; Li, Lei O et al. (2011) Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: relevance to valproate's efficacy against bipolar disorder. Biochim Biophys Acta 1811:163-9
Greenberg, Andrew S; Coleman, Rosalind A (2011) Expanding roles for lipid droplets. Trends Endocrinol Metab 22:195-6
Stapleton, Cliona M; Mashek, Douglas G; Wang, Shuli et al. (2011) Lysophosphatidic acid activates peroxisome proliferator activated receptor-? in CHO cells that over-express glycerol 3-phosphate acyltransferase-1. PLoS One 6:e18932

Showing the most recent 10 out of 33 publications