Department of Pharmacology Faculty
George A. Cook, Ph.D.
Room 303 Crowe Research Building
- Auburn University, B.S. 1967, Zoology
- Auburn University, Ph.D., 1974, Biochemistry
- Oklahoma Medical Research Foundation, Post-Doc., Biochemistry
Research in this laboratory has been concerned with investigating the regulation of fatty acid oxidation and fat transport. Our primary interest is in the regulation of two genes that encode two isoforms of the enzyme Carnitine Palmitoyltransferase-I (CPT-I) which are located in the mitochondrial outer membrane. These enzymes are widely recognized as important control points for the fatty acid oxidation pathway in several organs. CPT-I<alpha> is the gene expressed in most tissues in mammals while CPT-I<beta> is expressed in muscle cells and adipocytes. Interestingly, cardiac ventricular myocytes are the only cells in which both isoforms are expressed. These enzymes regulate mitochondrial fatty acid oxidation through various mechanisms in different tissues. Our earlier work in this area focused on mechanisms causing changes in enzyme activity and inhibitory sensitivity to malonyl-CoA, the physiological inhibitor of CPT-I. Several disease states (diabetes, hyperthyroidism, etc.) produce altered inhibitory sensitivity of CPT-I which we have shown to be caused by changes in membrane phospholipids through the actions of insulin and thyroid hormone. These hormonal changes are the major regulators in liver that control the production of ketone bodies and the export of the lipoprotein VLDL.
Recently our main research interest has been the transcriptional regulation of the CPT-I<alpha> and CPT-I<beta> genes in cardiac myocytes, liver and skeletal muscles in which three different expression patterns are controlled by at least four regulatory elements in the promoters and first introns of these genes. Understanding transcriptional regulation of the CPT-I isoforms in the liver and heart is important for understanding normal perinatal development as well as adverse control of fatty acid oxidation in disease states that include Type I and Type II diabetes, altered thyroid states, cardiac hypertrophy and heart failure. We are currently investigating the hormonal and transcriptional regulation of the CPT-I<alpha> and CPT-I<beta>) genes in the heart where these two isoenzymes regulate the proportion of energy derived from fatty acids vs. glucose used by the heart for muscle contraction under various physiological and pathophysiological conditions. The failure of the differential control mechanisms of the two genes in the heart is important in the development of cardiac hypertrophy leading to heart failure and in diabetic cardiomyopathy.