Last Updated: 4/25/2008

Research Interests
Regulation and mechanism of action of enzymes that synthesize triacylglycerol. We are investigating the relationship between triacylglycerol synthesis and disorders like diabetes, atherosclerosis, and obesity. In order to understand how triacylglycerol synthesis is regulated during normal physiological states such as feeding, fasting, and the neonatal period, we have focused on the initial and committed step, the acylation of sn-glycerol-3-P by glycerol-3-phosphate acyltransferase (GPAT). We are determining 1) the structural aspects of mitochondrial GPAT that contribute to its specificity and regulation; 2) the phosphorylation sites that regulate mitochondrial GPAT activity; 3) the function and specificity of mitochondrial GPAT's lipid cofactors; 4) the role of mitochondrial GPAT in directing the fate of fatty acids during different nutritional and hormonal states; and 5) the phenotype of mice constructed to be deficient in mitochondrial GPAT. Answers to these questions will allow us to understand how GPAT functions in cells to partition acyl-CoAs towards glycerolipid synthesis and away from beta-oxidation and how cells regulate their triacylglycerol content.

Signaling by lipid intermediates. Increasing or decreasing GPAT activity or the activity of several of the five long-chain acyl-CoA synthestase (ACSL) isoforms results in changes in tissue concentration of the signaling molecules LPA, PAS, acyl-CoA, and DAG. We have initiated studies on altered signaling in cells and organs with different expression of these enzymes. Recent papers show upregulation of GPAT1, ACSL4 and ACSL5 in colon and breast cancer. Upregulation suggests either that cancer cell proliferation requires increased synthesis of membrane precursors or that the signaling by LPA, etc. is critical.

Supporting this idea are our recent studies comparing DEN-induced tumors in wildtype versus mice deficient in GPAT1. The GPAT1-/- mice developed fewer and less advanced hepatic tumors (adenomas and carcinomas) than the wildtype mice.

Recent Accomplishments and Honors
Osbourn and Mendel Award from the American Society for Nutritional Sciences (given for recent basic science advances in nutrition)
Dr. Albert G. Hogan Memorial Lecturer for 2008, University of Missouri.
Working on Women in Science Scholar, UNC School of Medicine (2008-10).
Delta Omega Faculty Award (2008)

Publications
Coleman RA, Lewin TM, Van Horn CG, and Gonzalez-Bar MR. Do acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? (2002) J. Nutr. 132:2123-2126.

Lewin TM, Van Horn CG, Krisans SK, and Coleman RA. Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes and mitochondrial associated membrane (2002) Arch. Biochem. Biophys. 404:263-270.

Hammond, L.E., Gallagher, P.A., Wang, S., Hiller, S., Kluckman, K.D., Posey-Marcos, E.L., Maeda, N. and Coleman, R.A. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition (2002) Mol. Cell. Biol. 22:8204-8214

Caviglia, JM., Li, L, Wang, S, DiRusso, CC, Coleman, RA and Lewin, TM. Rat long-chain acyl-CoA synthetase 5, but not 1, 2, 3, or 4 complements Escherichia coli fadD (2004), J. Biol. Chem. 279: 11163 - 11169

Lewin, TM, Schwerbrock, NMJ., Lee, DP, and Coleman, RA. Identification of a new glycerol-3-phosphate acyltransferase isoenzyme, mtGPAT2, in mitochondria (2004) J. Biol. Chem. 279:13488-13495

Lewin, TM, Wang, S, Nagle, CA, Van Horn, CG, and Coleman, RA. Mitochondrial glycerol-3-phosphate acyltransferase-1 directs the metabolic fate of exogenous fatty acids in hepatocytes (2005) Am. J. Physiol. Endocrinol. Metab. 288: E835-E844

Van Horn, CG, Caviglia, JM, Li, LO, Wang, S, Granger, DA, and Coleman, RA. Characterization of recombinant long-chain rat acyl-CoA synthetase isoforms 3 and 6: Identification of a novel variant of isoform 6 (2005) Biochemistry 44:1635-1642.

Hammond, LE, Neschen, S, Romanelli, AJ, Cline, GW, Ilkayeva, OR, Shulman, GI, Muoio, DM, and Coleman, RA. Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential for the metabolism of excess acyl-CoAs, (2005) J. Biol. Chem. 280: 25629-25636

Neschen, S, Morino, K, Hammond, LE, Zhang, D, Liu, Z-X, Romanelli, AJ, Cline, GW, Pongratz, RL, Zhang, XM, Choi, CS, Coleman, RA, and Shulman, GI. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knock out mice. (2005) Cell Metab. 2:55-65

Pellon-Maison, M., Coleman, R.A., and Gonzalez-Baró, M.R. The C-terminal region of mitochondrial glycerol 3-phosphate acyltransferase-1 interacts with the active site region and is required for activity, (2006) Arch. Biochem. Biophys. 450:157-166

Tong, F., Black, P.N., Coleman, R.A. and DiRusso, C.C. Evidence Rat ACSL1, 4, and 6 but not ACSL5 participate in fatty acid transport by vectorial acylation (2006) Arch. Biochem. Biophys. 447:46-52

Beigneux, A.P., Vergnes, L., Qiao, X., Quatela, S., Davis, R., Watkins, S.M., Coleman, R.A., Walzem, R.L., Philips, M., Reue, K., and Young, S.G., Agpat6 - a novel lipid biosynthetic gene required for triglyceride production in mammary epithelium (2006) J. Lipid Res. 47: 734-744

Mashek, D.G., Li, L.O., and Coleman, R.A. Rat long chain acyl-CoA synthetase mRNA, protein and activity vary in tissue distribution and in response to diet (2006) J. Lipid Res. 47:2004-2010

Li, L.O., Mashek, D.G., Jie, A., Doughman, S.D., Newgard, C.B. and Coleman, R.A. Rat long chain acyl-CoA synthetase 1 channels fatty acids toward reesterification to triacylglycerol and phospholipids and away from -oxidation (2006) J. Biol. Chem. 281: 37246-37255

DeJong, H, Neal, AC, Coleman, RA, and Lewin, TM. Ontogeny of mRNA expression and activity of long-chain acyl-CoA synthetase (ACSL) isoforms in Mus musculus heart (2007) Biochim. Biophys. Acta, 1771:75-82.

Stinnett, L., Lewin, T.M. and Coleman, R.A. Mutagenesis of rat acyl-CoA synthetase 4 indicates an extended fatty acid binding site (2007) Biochim. Biophys. Acta, 1771:119-125

Hammond, L.E., Albright, C.D., He, L., Rusyn, I., Watkins, S.M., Doughman, S.D., Lemasters, J.J., and Coleman, R.A. Increased mitochondrial oxidative stress in the GPAT-/- mouse leads to balanced increases in hepatocyte apoptosis and proliferation and a decrease in GST positive cells, (2007) Exper. Molec. Pathol. 82(2):210-219

Nagle, C.A., An, J., Shiota, M., Torres, T.P., Cline, G.W., Liu, Z-X., Wang, S., Catlin, R.L., Shulman, G.I., Newgard, C.B., and Coleman, R.A. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance (2007) J. Biol. Chem. 282:14807-14815

Wang, S., Lee, D.P., Gong, N., Schwerbrock, N.M.J., Mashek, D.G., Gonzalez-Baró, M.R., Stapleton, C.M., Li, L.O., Lewin, T.M., and Coleman, R.A. Cloning and functional characterization of a novel mitochondrial N-ethylmaleimide-sensitive glycerol-3-phosphate acyltransferase (GPAT2) (2007) Arch. Biochem. Biophys. 465:347-358

Askari, B., Kanter, J.E., Sherrid, A.M., Golej, D.L., Bender, A.T., Beavo, J.A., Coleman, R.A., and Bornfeldt, K.E. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to cellular triacylglycerol via a PPARγ-independent mechanism in human arterial smooth muscle cells and macrophages (2007) Diabetes, 56:1143-1152

Pellon-Maison, M., Montanaro, M.A., Coleman, R.A. and Gonzalez-Baró, M.R. Mitochondrial glycerol-3-P acyltransferase 1 is most active in outer mitochondrial membrane but not in mitochondrial associated vesicles (MAV) (2007) Biochim, Biophys. Acta, 1771:830-838

Nagle, C.A., Vergnes, L., DeJong, H., Wang, S., Lewin, T.M., Reue, K. and Coleman, R.A. Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4 as the enzyme deficient in Agpat6—/— mice (2008) J. Lipid Res. 49:823-31

E-mail: rcoleman@unc.edu
Telephone: (919) 966-7213
FAX: (919) 966-7216
Address: 2209 McGavran Greenberg Hall Chapel Hill, NC

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