Hormonal Regulation of Fatty Acid Oxidation

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DESCRIPTION (provided by applicant): The metabolism of long chain fatty acids is profoundly altered in diabetes and hyperthyroidism. Carnitine palmitoyltransferase I (CPT-I) regulates the entry of long chain fatty acids into mitochondria and is a rate controlling step in the pathway of fatty acid oxidation. We have examined both the "liver" (CPT-Ialpha) and "muscle" (CPT-Ibeta) isoforms of CPT-I in the liver and heart respectively. Studies from our laboratory have demonstrated that CPT-Ialpha activity and gene expression are elevated in diabetes and hyperthyroidism. Our overall goal is to understand the mechanisms by which the expression of CPT-I gene isoforms and mitochondrial fatty acid oxidation are stimulated in these states. The peroxisomal proliferator activated receptor gamma coactivator-1 (PGC-1) is a transcriptional coactivator that promotes mitochondrial biogenesis. PGC-1 is expressed in metabolically active tissues such as the heart and liver. We propose to investigate the role of PGC-1 in the induction of CPT-I genes. Recently we have discovered that PGC-1 enhances CPT-Ialpha gene expression. In the liver, the abundance of PGC- 1 is increased in diabetes and by thyroid hormone (T3). In these studies, we will investigate the role of PGC-1 in regulating fatty acid oxidation and define the mechanisms through which PGC-I stimulates CPT-Ialpha gene expression. T3 is a key regulator of lipid metabolism. We have identified a thyroid hormone response element in the CPT-Ialpha promoter and discovered that elements within the first intron are crucial for liver specific induction by T3. We will define the unique role of the first intron in the T3 induction of CPT-Ialpha gene expression. Fatty acids are a primary source of energy for cardiac myocytes, and fatty acid oxidation is increased at the expense of glucose utilization in the diabetic heart. PGC-1 stimulates CPT-Ibeta gene expression. We will examine the mechanisms by which PGC-1 stimulates CPT-Ibeta gene expression in the heart. Disorders of lipid and glucose metabolism contribute to a number of clinical complications observed in diabetes and altered thyroid states. This proposal will examine novel molecular mechanism underlying alterations in the gene expression of critical enzymes in the mitochondrial pathway of beta-oxidation.