The long-term goals of our research are to understand how hepatic glycerolipid synthesis contributes to disorders like obesity, diabetes, atherosclerosis, and how triacylglycerol synthesis is regulated. The proposed studies for this renewal focus primarily on the role, requirement, structure and function of the initial and committed step in the pathway of triacylglycerol synthesis, the acylation of sn-glycerol-3-P by glycerol-3- phosphate acyltransferase (GPAT). Our recent data, provided by over-expression studies and studies in knockout mice, suggest that the mitochondrial GPAT isoform (mtGPAT) 1) directs exogenous fatty acids towards triacylglycerol synthesis and away from oxidation and 2) directly controls the amount of palmitate in the sn-1 position of glycerolipids and indirectly controls the amount of arachidonate at the sn-2 position. These findings have implications regarding obesity, insulin resistance and eicosanoid production. We will determine 1) how mtGPAT is regulated by phosphorylation; 2) how mtGPAT knockout mice are protected against insulin resistance and obesity 3) whether mtGPAT and CPT-1 directly compete for acyI-CoAs at the mitochondrial membrane; and 4) what the consequence of absent mtGPAT is in hepatocytes, inflammatory cells and brain. Answers to these questions will allow us to understand how mtGPAT functions in cells to partition acyI-CoAs towards glycerolipid synthesis and away from beta-oxidation, how cells regulate their triacylglycerol content, and what the implications are for the normal positioning of fatty acids in glycerolipids. The information gained could lead to advances in the therapy of disorders characterized by abnormal regulation of VLDL synthesis or triacylglycerol storage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK056598-19
Application #
6616644
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1985-04-01
Project End
2007-02-28
Budget Start
2003-04-16
Budget End
2004-02-29
Support Year
19
Fiscal Year
2003
Total Cost
$328,089
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Nutrition
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
Tavian, D; Missaglia, S; Castagnetta, M et al. (2017) Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM. Mol Genet Metab 121:28-34
Pagac, Martin; Cooper, Daniel E; Qi, Yanfei et al. (2016) SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase. Cell Rep 17:1546-1559
Pascual, Florencia; Coleman, Rosalind A (2016) Fuel availability and fate in cardiac metabolism: A tale of two substrates. Biochim Biophys Acta 1861:1425-33
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
Cooper, Daniel E; Grevengoed, Trisha J; Klett, Eric L et al. (2015) Glycerol-3-phosphate Acyltransferase Isoform-4 (GPAT4) Limits Oxidation of Exogenous Fatty Acids in Brown Adipocytes. J Biol Chem 290:15112-20
Zhang, Chongben; Hwarng, Gwen; Cooper, Daniel E et al. (2015) Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. J Biol Chem 290:3519-28
Garcia-Fabiani, Maria B; Montanaro, Mauro A; Lacunza, Ezequiel et al. (2015) Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis. Biochem J 471:211-20
Zhang, Chongben; Cooper, Daniel E; Grevengoed, Trisha J et al. (2014) Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor. Am J Physiol Endocrinol Metab 307:E305-15
Pellon-Maison, Magali; Montanaro, Mauro A; Lacunza, Ezequiel et al. (2014) Glycerol-3-phosphate acyltranferase-2 behaves as a cancer testis gene and promotes growth and tumorigenicity of the breast cancer MDA-MB-231 cell line. PLoS One 9:e100896

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