Department of Pharmacology Faculty
Edwards A. Park, Ph.D.
Room 311 Crowe Research Building
- Duke University, Durham, NC, B.A., 1977, History
- Pennsylvania State University, Hershey, PA, Ph.D., 1984, Physiology
- Case Western Reserve University, Cleveland, OH Postdoc., 1991, Biochemistry/Molecular Biology
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.
Shulan Song, M.D.
Sara Cannaughton, B.S.
Farhana Chowdhury, Ph.D.
Current Graduate Students: