Hormonal Regulation of Fatty Acid Oxidation

描述（由申请人提供）：糖尿病和甲状腺功能亢进症患者的长链脂肪酸代谢发生了深刻变化。肉毒碱棕榈酰转移酶I（CPT-I）调节长链脂肪酸进入线粒体，并且是脂肪酸氧化途径中的速率控制步骤。我们已经分别检查了肝脏和心脏中CPT-I的“肝脏”（CPT-I α）和“肌肉”（CPT-I β）亚型。我们实验室的研究表明，CPT-Ⅰ α活性和基因表达在糖尿病和甲状腺功能亢进症中升高。我们的总体目标是了解CPT-I基因亚型的表达和线粒体脂肪酸氧化在这些状态下被刺激的机制。过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1）是促进线粒体生物合成的转录共激活因子。PGC-1在代谢活性组织如心脏和肝脏中表达。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可增强CPT-1 α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）中增加。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-1刺激CPT-1 α基因表达的机制。T3是脂质代谢的关键调节因子。我们已经确定了CPT-Ⅰ α启动子中的甲状腺激素反应元件，并发现第一内含子内的元件对T3的肝脏特异性诱导至关重要。我们将确定的独特作用的第一内含子在T3诱导CPT-Ⅰ α基因的表达。脂肪酸是心肌细胞的主要能量来源，并且脂肪酸氧化以糖尿病心脏中葡萄糖利用为代价而增加。PGC-1刺激CPT-1 β基因表达。我们将研究PGC-1刺激心脏中CPT-1 β基因表达的机制。脂质和葡萄糖代谢紊乱导致在糖尿病和甲状腺状态改变中观察到的许多临床并发症。该提案将研究线粒体β-氧化途径中关键酶基因表达改变的新分子机制。

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.