Hormonal Regulation of Fatty Acid Oxidation

描述(申请人提供)：在糖尿病和甲亢中，长链脂肪酸的新陈代谢发生了深刻的变化。肉碱棕榈酰转移酶I(CPT-I)调节长链脂肪酸进入线粒体，是脂肪酸氧化途径中的一个速率控制步骤。我们分别检测了肝脏和心脏中CPT-I的“肝脏”(CPT-Ipha)和“肌肉”(CPT-Ibeta)异构体。我们实验室的研究表明，在糖尿病和甲状腺功能亢进症中，CPT-Ipha活性和基因表达增加。我们的总体目标是了解CPT-I基因异构体的表达和线粒体脂肪酸氧化在这些状态下被刺激的机制。过氧化体增殖物激活受体-1(PGC-1)是一种促进线粒体生物发生的转录共激活因子。PGC-1在新陈代谢活跃的组织中表达，如心脏和肝脏。我们建议研究PGC-1在CPT-I基因诱导中的作用。最近我们发现PGC-1能增强CPT-Ipha基因的表达。在肝脏中，PGC-1的丰度在糖尿病和甲状腺激素(T3)的作用下增加。在这些研究中，我们将研究PGC-1在调节脂肪酸氧化中的作用，并确定PGC-I刺激CPT-Ipha基因表达的机制。T3是脂代谢的关键调节因子。我们已经确定了CPT-Ipha启动子中的甲状腺激素反应元件，并发现第一内含子中的元件对于T3诱导肝脏特异性起关键作用。我们将确定第一内含子在T3诱导CPT-Ipha基因表达中的独特作用。脂肪酸是心肌细胞的主要能量来源，而在糖尿病心脏中，脂肪酸氧化是以牺牲葡萄糖利用为代价的。PGC-1刺激CPT-Ibeta基因表达。我们将研究PGC-1刺激心脏CPT-Ibeta基因表达的机制。在糖尿病和甲状腺状态改变中观察到的许多临床并发症都是由脂肪和葡萄糖代谢紊乱引起的。这项提议将研究线粒体β-氧化途径中关键酶基因表达变化的新的分子机制。

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.