Regulation of metabolic gene expression

代谢基因表达的调控

• 批准号: 7371181
• 负责人: Edwards A Park
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371181
• 关键词: Abbreviations; Acetyl Coenzyme A; Acyl Coenzyme A; Address; Amino Acids; Animals; Biogenesis; Carnitine; Carnitine Acyltransferases; Carnitine O-Palmitoyltransferase; Carnitine Palmitoyltransferase I; Carnitine Palmitoyltransferase II; Cell Respiration; Clinical; Coenzyme A; Data; Development; Disease; Disruption; Elements; Elevation; Enzymes; Estrogens; Fatty Acids; Fatty Liver; Figs - dietary; Fish Oils; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glucocorticoids; Gluconeogenesis; Glucose; Goals; Hepatic; Hepatocyte; Hyperglycemia; Hyperlipidemia; Incidence; Insulin; Insulin Resistance; Leucine; Lipids; Liver; Malonyl Coenzyme A; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Carnitine Palmitoyltransferase Pathway; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Orphan Receptor; Nuclear Receptors; Obesity; Oxidative Phosphorylation; PDH kinase; PPAR gamma; Pathway interactions; Patients; Peptides; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Phosphoenolpyruvate Carboxylase; Phosphorylation; Platelet Factor 4; Protein Isoforms; Proteins; Public Health; Pyruvate; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase; Pyruvate Dehydrogenase Complex; Pyruvate Metabolism Pathway; Pyruvates; Rate; Regulation; Rodent; Role; System; Testing; Transcriptional Activation; Triglycerides; Very Long Chain Fatty Acid; acyl-CoA dehydrogenase; acyl-CoA oxidase; blood glucose regulation; fatty acid oxidation; forkhead protein; gene induction; glucose production; hepatic gluconeogenesis; hormone regulation; insight; long chain fatty acid; malonyl-CoA decarboxylase; novel; oxidation; peroxisome; promoter; receptor; therapeutic target; transcription factor

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.

描述（由申请人提供）：肥胖、胰岛素抵抗和2型糖尿病的发病率在世界范围内急剧增加。在胰岛素抵抗的情况下观察到的高血糖症，部分是由于肝葡萄糖生成增加（糖原生成）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并促进甘油三酯合成，导致肝脂肪变性。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途径中关键基因的调控。PGC-1？？刺激参与脂肪酸氧化和肝再生的基因的表达，同时减少葡萄糖氧化。PGC-1？？调节基因表达的一部分，通过与核受体的相互作用，和PGC-1？？在胰岛素抵抗动物的肝脏中水平升高。丙酮酸脱氢酶复合物（PDC）催化丙酮酸转化为乙酰辅酶A。PDC被丙酮酸脱氢酶激酶（PDK）磷酸化使PDC失活。PDC是葡萄糖和丙酮酸氧化为乙酰辅酶A的高度调节的酶促步骤。我们已经发现PGC-1？？与雌激素相关受体（ERR？）诱导肝细胞中的PDK 4基因。呃？？是诱导肌肉中脂肪酸氧化的孤儿核受体。我们将研究胰岛素抑制PGC-1诱导PDK 4的机制。所以，ERR？我们将研究几个方面的PGC-1？？介导的肝脂肪酸氧化诱导。首先，我们将调查的肉毒碱棕榈酰转移酶（CPT）系统的直接诱导PGC-1？所以，ERR？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中的起始酶，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）。将确定PGC-1是否升高MCD？导致肝线粒体脂肪酸氧化增加。超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过氧化物酶体基因，诱导PGC-1？？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。总体而言，这些研究将为PGC-1？调控控制葡萄糖和脂质氧化的基因提供新的见解。 公共卫生关系：脂肪酸、葡萄糖和丙酮酸的代谢紊乱导致肥胖和胰岛素抵抗的并发症。我们的研究将确定PGC-1控制代谢的机制，并将增加我们对减少肝脏胰岛素抵抗的治疗的理解。通过激活PGC-1促进脂肪酸氧化可以通过减少与胰岛素抵抗升高和线粒体功能降低直接相关的肝脂肪变性而具有有益的临床影响。