Regulation of metabolic gene expression

描述(申请人提供)：肥胖、胰岛素抵抗和2型糖尿病的发病率在全球范围内急剧增加。胰岛素抵抗时观察到的高血糖，部分原因是肝脏葡萄糖生成增加(糖异生)。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和促进甘油三酯合成，导致肝脏脂肪变性。这些代谢紊乱中的许多部分是由基因表达的变化引起的。我们的研究将探讨在脂肪酸氧化和丙酮酸代谢途径中关键基因的调节作用。PGC-1可刺激与脂肪酸氧化和肝脏糖异生有关的基因表达，同时减少葡萄糖氧化。PGC-1在一定程度上通过与核受体的相互作用来调节基因表达，在胰岛素抵抗动物的肝脏中PGC-1水平升高。丙酮酸脱氢酶复合体(PDC)催化丙酮酸转化为乙酰辅酶A。丙酮酸脱氢酶(PDK)对PDC的磷酸化可使PDC失活。PDC是葡萄糖和丙酮酸氧化为乙酰辅酶A的一个高度受调控的酶步骤。我们发现PGC-1与雌激素相关受体(ERR？)诱导肝细胞中的PDK4基因。Err？？是一种孤立的核受体，可以诱导肌肉中的脂肪酸氧化。我们将探讨胰岛素抑制PGC-1和ERR？诱导的PDK4的机制。我们将研究PGC-1？？介导的诱导肝脏脂肪酸氧化的几个方面。首先，我们将研究PGC-1和ERR？对肉毒碱棕榈酰转移酶(CPT)系统的直接诱导作用。CPT系统控制长链脂肪酸进入线粒体进行氧化。Cpt-I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能刺激丙二酰辅酶A脱羧酶(MCD)。将确定PGC-1？？升高MCD是否导致肝脏线粒体脂肪酸氧化增加。超长链脂肪酸和鱼油在过氧化体中被氧化。我们已经确定了几个由PGC-1诱导的过氧化体基因，并将研究PGC-1在刺激超长链脂肪酸的过氧体氧化中的新作用。总体而言，这些研究将为PGC-1对控制糖脂氧化的基因的调控提供新的见解。 公共卫生相关性：脂肪、葡萄糖和丙酮酸代谢紊乱会导致肥胖和胰岛素抵抗的并发症。我们的研究将确定PGC-1控制新陈代谢的机制，并将增加我们对针对降低肝脏胰岛素抵抗的治疗的理解。通过激活PGC-1来促进脂肪酸氧化可能通过减轻肝脏脂肪变性而产生有益的临床影响，而脂肪变性直接与胰岛素抵抗增加和线粒体功能降低有关。

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.