Regulation of metabolic gene expression

简介（由申请人提供）：肥胖症、胰岛素抵抗和2型糖尿病的发病率在世界范围内急剧上升。在胰岛素抵抗中观察到的高血糖，部分是由于肝脏葡萄糖生成增加（糖异生）引起的。然而，在胰岛素抵抗患者的肝脏中，胰岛素矛盾地继续抑制脂肪酸氧化，促进甘油三酯合成，导致肝脏脂肪变性。许多这些代谢紊乱部分源于基因表达的变化。我们的研究将探讨过氧化物酶体增殖物激活受体γ辅激活因子（PGC-1?）对脂肪酸氧化和丙酮酸代谢通路中关键基因的调控。PGC-1 ? ?刺激参与脂肪酸氧化和肝脏糖异生的基因表达，同时减少葡萄糖氧化。PGC-1 ? ?部分通过与核受体和PGC-1的相互作用调节基因表达。胰岛素抵抗动物肝脏中的水平升高。丙酮酸脱氢酶复合物（PDC）催化丙酮酸转化为乙酰辅酶a。丙酮酸脱氢酶激酶（PDK）对PDC的磷酸化使PDC失活。PDC是葡萄糖和丙酮酸氧化成乙酰辅酶a的一个高度调控的酶促步骤。我们发现PGC-1?？与雌激素相关受体（ERR?）联合诱导肝细胞中的PDK4基因。犯错? ?是一种罕见的核受体，在肌肉中诱导脂肪酸氧化。我们将研究胰岛素抑制PGC-1诱导PDK4的机制。和犯错?。我们将研究PGC-1的几个方面？介导的肝脂肪酸氧化诱导。首先，我们将研究PGC-1对肉碱棕榈酰转移酶（CPT）系统的直接诱导作用。和犯错?。CPT系统控制长链脂肪酸进入线粒体进行氧化。cpt - 1是脂肪酸转运到线粒体的起始酶，被丙二酰辅酶a抑制。我们发现PGC-1?？刺激丙二酰辅酶a脱羧酶（MCD）PGC-1对MCD升高的影响有助于增加肝脏线粒体脂肪酸氧化。长链脂肪酸和鱼油在过氧化物酶体中被氧化。我们已经确定了几个由PGC-1诱导的过氧化物酶体基因。并将研究PGC-1的新作用？？刺激长链脂肪酸的过氧化物酶体氧化。总的来说，这些研究将为PGC-1调控葡萄糖和脂质氧化的基因提供新的见解。

DESCRIPTION (provided by applicant): The incidence of obesity, insulin resistance and type 2 diabetes is increasing dramatically world wide. The hyperglycemia, observed with insulin resistance, arises in part from increased hepatic glucose production (gluconeogenesis). However in the liver of insulin resistant patients, insulin paradoxically continues to inhibit fatty acid oxidation and promote triglyceride synthesis leading to hepatic steatosis. Many of these metabolic derangements arise in part from changes in gene expression. Our studies will investigate the regulation of key genes in the pathways of fatty acid oxidation and pyruvate metabolism by the peroxisome proliferator activated receptor gamma coactivator (PGC-1?). PGC-1??stimulates the expression of genes involved in fatty acid oxidation and hepatic gluconeogenesis while reducing glucose oxidation. PGC-1??regulates gene expression in part through interactions with nuclear receptors, and PGC-1??levels are elevated in the livers of insulin resistant animals. The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA. The phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK) inactivates PDC. PDC is a highly regulated enzymatic step in the oxidation of glucose and pyruvate to acetyl-CoA. We have found that PGC-1??in conjunction with the estrogen related receptor (ERR?) induces the PDK4 gene in hepatocytes. ERR??is an orphan nuclear receptor that induces fatty acid oxidation in muscle. We will investigate the mechanisms by which insulin inhibits the induction of PDK4 by PGC-1??and ERR?. We will examine several aspects of the PGC-1??mediated induction of hepatic fatty acid oxidation. First, we will investigate the direct induction of the carnitine palmitoyltransferase (CPT) system by PGC-1??and ERR?. The CPT system controls the entry of long chain fatty acids into mitochondria for ¿-oxidation. CPT-I, which is the initiating enzyme in fatty acid translocation into mitochondria, is inhibited by malonyl-CoA. We found that PGC-1??stimulates malonyl-CoA decarboxylase (MCD). It will be determined if the elevation of MCD by PGC-1??contributes to increased hepatic mitochondrial fatty acid oxidation. Very long chain fatty acids and fish oils are oxidized in peroxisomes. We have identified several peroxisomal genes that are induced by PGC-1??and will examine the novel role of PGC-1??in stimulating the peroxisomal oxidation of very long chain fatty acids. Overall, these studies will provide new insights into the regulation of genes controlling glucose and lipid oxidation by PGC-1?. PUBLIC HEALTH RELEVANCE: Disorders in the metabolism of fatty aicds, glucose and pyruvate contribute to the complications of obesity and insulin resistance. Our studies will define mechanisms by which PGC-1 controls metabolism and will add to our understanding of therapies directed towards the reduction of hepatic insulin resistance. Enhancing fatty acid oxidation by activating PGC-1??could have a beneficial clinical impact by reducing hepatic steatosis which is directly associated with elevated insulin resistance and decreased mitochondrial function.