Edwards A. Park, Ph.D.
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Education:Duke University, Durham, NC, B.A., 1977, History Research Interests:Our laboratory examines the hormonal and dietary regulation of genes involved in fatty acid, glucose and pyruvate metabolism. We are investigating the mechanisms by which specific nuclear receptors and transcription factors are modulated by hormones and nutrients to alter the expression of genes encoding metabolic enzymes. Our studies will define mechanisms by which altered expression of specific genes contributes to the pathophysiology of type 2 diabetes, obesity and thyroid disorders. The hormones which we have investigated most extensively are thyroid hormone (T3), glucocorticoids, long chain fatty acids (LCFA) and insulin. One gene that we are studying encodes carnitine palmitoyltransferase (CPT-1a). CPT-1a is a controlling step in the pathway of mitochondrial oxidation of long chain fatty acids. Our second gene of interest is the pyruvate dehydrogenase kinase 4 (PDK4) gene. Pyruvate is metabolized to acetyl-CoA by pyruvate dehydrogenase (PDC), and PDK4 will inhibit PDC by phosphorylation. If PDC is inhibited via PDK4 mediated phosphorylation, pyruvate can be converted to lactate or enter the gluconeogenic pathway. Gluconeogenesis is the process by which glucose is synthesized from precursors such as pyruvate, lactate and alanine. Gluconeogenesis contributes to the hyperglycemia of diabetes. Our hypothesis is that changes in gene expression contribute to the phenotype of insulin resistance and type 2 diabetes. We are working to understand the mechanisms controlling changes in gene transcription T3, glucocorticoids and LCFA activate specific nuclear receptors including the TR, GR and PPARa (peroxisome proliferators activated receptor for LCFA). The liganded nuclear receptors bind to target gene promoters and modulate gene expression. Both the CPT-Ia and PDK4 genes are induced by T3, high fat diets and glucocorticoids. CPT-Ia and PDK4 are regulated in a similar manner by hormones but the mechanisms by which they are controlled are different. Insulin inhibits the expression of both these genes, and a major interest of our laboratory is how insulin inhibits gene expression. With insulin resistance in the liver, there is an increase in hepatic glucose output but paradoxically fatty acid oxidation is suppressed in junction with elevated fatty acid synthesis. To analyze the mechanisms by which hormones regulate gene expression, we are examining the promoters of the PDK4 and CPT-1a genes. Currently, we are identifying transcription factors and nuclear receptors that are involved in the stimulation of CPT-1a transcription by hormones and LCFA as well as the inhibition of expression by insulin. Most recently, we have focused on the role of a specific coactivator PGC-1 in the regulation of the CPT-1a and PDK4 genes. Liganded nuclear receptors recruit coactivators such as PGC-1 to help activate gene expression. Our studies have defined a role for PGC-1 in fatty acid oxidation and pyruvate oxidation. We are investigating how coactivators will interact with nuclear receptors to mediate hormone responses. In summary, our studies are focused on the molecular mechanisms by which hormones regulate the expression of genes. We are particularly interested in hormones and genes involved in the regulation of energy metabolism.
Selected Publications:L.A. Jurado, S. Song, W.J. Roesler and E.A. Park. Conserved amino acids within CCAAT enhancer binding proteins (C/EBPa and ß) regulate phosphoenolpyrvate carboxykinase (PEPCK) gene expression. J. Biol. Chem. 277: 27606-27612, 2002. X. Deng, L.M. Cagen, H.G. Wilcox, E.A. Park, R. Raghow and M.B. Elam. Regulation of the rat SREBP-1 promoter in primary rat hepatocytes. Biochem. Biophys. Res. Comm. 290: 256-262, 2002. L. Jackson-Hayes, S. Song, E.N. Lavrentyev, M.S. Jansen, F.B. Hillgartner, L. Tian, P.A. Wood, G.A. Cook and E.A. Park. A thyroid hormone response unit formed between the promoter and first intron of the carnitine palmitoyltransferase-Ia gene mediates the liver specific induction by thyroid hormone. J Biol. Chem. 278: 7964-7972, 2003. M.L. Moore, E.A. Park and J.B. McMillin. Upstream Stimulatory Factor Represses the Induction of Carnitine Palmitoyltransferase-Iß Expression by PGC-1. J. Biol. Chem.278: 17263-17268, 2003. S. Song, Y. Zhang, K. Ma, L. Jackson-Hayes, E.N. Lavrentyev, G.A. Cook, M.B. Elam and E.A. Park. Peroxisomal proliferator activated receptor gamma coactivator (PGC-1a) stimulates carnitine palmitoyltransferase I (CPT-Ia) through the first intron., Biochem. Biophys. Acta, 1679: 164-73, 2004. X. Deng, M.B. Elam, H.G. Wilcox, L.M. Cagen, E.A. Park, R. Raghow, D. Patel, P. Kumar and J.C. Russell. Dietary fatty acids mitigate induction of lipogenic enzymes in the hyperinsulinemic corpulent JCR:LA-cp rat: Microarray profiling of lipid related gene expression. Endocrinology145: 5847-61, 2004. Y. Zhang, K. Ma, S. Song, M.B. Elam, G.A. Cook and E.A. Park. Peroxisomal proliferator activated receptor gamma coactivator (PGC-1a) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-Ia), J. Biol. Chem.J Biol Chem. 279: 53963-71, 2004. L.M. Cagen, X. Deng, H.G. Wilcox, E.A. Park, R. Raghow and M.B. Elam. Insulin activates the rat SREBP-1c promoter through the actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem. J.385: 207-16, 2005. Posttranslational processing of SREBP-1 in rat hepatocytes is regulated by insulin and cAMP. C.R. Yellaturu, X. Deng, L.M. Cagen , H.G. Wilcox, E.A. Park, R. Raghow, M.B. Elam. Biochem. Biophys. Res. Comm. 332:174–180, 2005. K. Ma, Y. Zhang, M.B. Elam, G.A. Cook and EA. Park. Cloning of the rat pyruvate dehydrogenase kinase 4 (PDK4) gene promoter: Activation of PDK4 by the peroxisome proliferator-activated receptor gamma coactivator (PGC-1a). J. Biol. Chem.280(33): 29525-32, 2005. Yi Zhang, Ke Ma, Stephanie Gaillard, Prabodh Sadana,Farhana Chowdhury,Donald P. McDonnell, Marshall B. Elam, and E.A. Park. Estrogen Related Receptors Stimulate Pyruvate Dehydrogenase Kinase Isoform 4 (PDK4) Gene Expression. J. Biol. Chem. 281:39897-906, 2006 Prabodh Sadana, Yi Zhang, Shulan Song, George A. Cook, Marshall B. Elam and E.A. Park. Regulation of hepatic carnitine palmitoyltransferase I (CPT-I) gene expression by the peroxisomal proliferator activated receptor gamma coactivator-1ß (PGC-1ß). Mol Cell Endocrinol. 267(1-2):6-16, 2007 Prabodh Sadana and E.A. Park. Characterization of the transactivation domain in the peroxisome proliferator activated receptor gamma coactivator (PGC-1). Biochem J. 403(3):511-8, 2007 Xiong Deng, Chandrahasa Yellaturu, Lauren Cagen, Henry G Wilcox, E.A. Park, Rajendra Raghow and Marshall B Elam. Expression of the rat sterol regulatory element binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1. J. Biol. Chem. 282(24):17517-29, 2007 Parker SL, Parker MS, Estes AM, Wong YY, Sah R, Sweatman T, Park EA, Balasubramaniam A, Sallee FR. The neuropeptide Y (NPY) Y2 receptors are largely dimeric in the kidney, but monomeric in the forebrain. J Recept Signal Transduct Res. 28(3):245-63, 2008 R. Raghow, C. Yellaturu, X. Deng, E.A. Park and M.B. Elam. SREBPs: Crossroads of physiological and pathological lipid homeostasis.. Trends Endocrinol Metab. 19(2):65-73, 2008 M.B. Elam, G.S. Cowan, M. L. Hiler, E.A. Park, I.C. Gerling, D. Patel, R.J. Rooney, J.C. Corton, L. Cagen, H. Wilcox, C. Yellaturu, X. Deng, M. Gandhi, M. Bahr, C. Allan, L. Wodi, G. Cook, T. Hughes, R. Raghow. Altered hepatic gene expression with massive weight loss following gastric bypass surgery in morbidly obese women: Implications for disease susceptibility in morbid obesity. In press, Int. J. Obesity, 2008 C.R. Yellataru, X. Deng, L. M. Cagen, H.G. Wilcox, E.A. Park, R. Raghow and M.B. Elam. Insulin Enhances Posttranslational Processing of Nascent SREBP-1c by Promoting its Phosphorylation and Association with COPII vesicles. J. Biol. Chem., in revision, 2008 M.B. Elam, C. Yellaturu, G.E. Howell, X. Deng, G.S. Cowan, P. Kumar, E.A. Park, D. Patel, R.J. Rooney, M.L. Hiler, H.G. Wilcox, T.A. Hughes, R. Raghow. Molecular consequences of morbid obesity and weight loss on human hepatic gene expression: Evidence for aberrant regulation of nuclear signaling and de novo lipogenesis. J. Lipid Res., submitted 2008
Laboratory roster:Research Associates/Fellows: Shulan Song, M.D. Sara Cannaughton, B.S. Farhana Chowdhury, Ph.D. Current Graduate Students: Ramy Attia
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