Hepatic Fatty Acid Metabolism and Insulin Resistance

肝脏脂肪酸代谢和胰岛素抵抗

基本信息

批准号：
7186729
负责人：
MAJA STEFANOVIC-RACIC
金额：
$ 12.66万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7186729
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Abbreviations Acyl Coenzyme A Address Adenoviruses Affect Animal Feed Animals Apolipoproteins B Biochemistry Biological Models Bos taurus Bovine Serum Albumin Bromides Carnitine O-Palmitoyltransferase Carnitine Palmitoyltransferase I Cattle Choline Clinical Investigator Coenzyme A Ligases Data Development Diabetes Mellitus Diazepam Binding Inhibitor Diet Disease Eagles Electron Microscopy Elevation Enzymes Esterification Ethanolamines Fasting Fatty Acids Fatty Liver Fatty acid glycerol esters Gene Delivery Glycerol-3-phosphate acyltransferase Goals Hepatic Hepatocyte Hypertriglyceridemia In Vitro Individual Insulin Resistance Intake Learning Levocarnitine Lipids Lipoproteins Liver Lysophospholipids Metabolic Metabolic Diseases Metabolic syndrome Methods Mitochondria Muscle Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Onset of illness Pathway interactions Phenotype Phosphatidate Phosphatase Phosphatidic Acid Plasma Protein Isoforms Protein Kinase C Protein Overexpression Rattus Research Research Personnel Role Serine Serum Skeletal Muscle Small Interfering RNA Techniques Testing Tetrazolium Therapeutic Time Tissues Training Triglyceride Metabolism Triglycerides Very low density lipoprotein Zucker Rats alpha-glycerophosphoric acid career density design diabetic diabetic rat diacylglycerol O-acyltransferase diphenyl ethanolamine experience fatty acid binding protein fatty acid metabolism fatty acid oxidation fatty acid-binding proteins feeding fetal gene delivery system human FAT protein improved in vivo insulin sensitivity ketogenesis lipid metabolism lysophosphatidic acid lysophosphatidic acid acyltransferase metabolic abnormality assessment novel oxidation prevent programs skills

项目摘要

DESCRIPTION (provided by applicant): Insulin resistance is a hallmark feature of type 2 diabetes mellitus (DM) and is also present in many obese individuals and the majority of those with the metabolic syndrome. Fasting plasma free fatty acids (FFA) are frequently elevated in these subjects and significant controversy surrounds the role of hepatic FFA oxidation in the development of insulin resistance. Previous studies have been limited by the absence of a specific activator of this pathway. However, our preliminary data demonstrate that this issue can be addressed directly for the first time by overexpression of the enzyme carnitine palmitoyltransferase I (CPT I), a major intracellular regulator of beta-oxidation. This proposal has two primary goals. The first is to provide the applicant with the skills necessary to become an independent clinical investigator in the field of lipid metabolism and type 2 DM. Training aims; 1. To expand the candidate's theoretical background in the biochemistry of metabolic disorders. 2. To gain experience in the design and interpretation of metabolic studies. 3. To learn many of the practical techniques necessary to pursue a career in metabolic research. The second goal is to perform novel research into the role of L-CPT I in hepatic fatty acid metabolism, particularly as it relates to the development of insulin resistance, liver steatosis and type 2 DM. Research aims: In Aim 1, we will test the hypothesis that increased activity of L-CPT I in hepatocytes in vitro will promote fatty acid oxidation, while reducing acyl-CoA esterification, intracellular triglyceride (TG) accumulation and very low-density lipoprotein (VLDL) secretion. In Aims 2, 3 and 4, CPT I will be overexpressed in vivo, in the liver of normal rats, high-fat fed obese/insulin resistant rats and ZDF obese/diabetic rats, respectively. Elevated hepatic L-CPT I is expected to have similar effects on lipid metabolism as proposed for in vitro studies. We hypothesize that such alterations will decrease or prevent lipid accumulation in the liver. This is expected to: (1) enhance insulin sensitivity in normal rats (Aim 2); (2) ameliorate the disregulation of liver fatty acid metabolism associated with the development of insulin resistance in the high-fat fed animals (Aim 3); and (3) prevent or reverse the abnormalities of fatty acid metabolism that accompany the fully diabetic phenotype in ZDF rats (Aim 4).

描述（由申请人提供）：胰岛素抵抗是2型糖尿病（DM）的标志性特征，也存在于许多肥胖个体中，大多数患有代谢综合征的人。在这些受试者中，禁食血浆无脂肪酸（FFA）经常升高，肝FFA氧化在胰岛素抵抗发展中的作用围绕着肝FFA氧化的作用。先前的研究受到了该途径的特定激活因子的限制。但是，我们的初步数据表明，可以通过过度表达Carnitine Palmitoyltransylansferase I（CPT I），这是首次直接解决此问题，这是Beta氧化的主要细胞内调节剂。该提议有两个主要目标。首先是为申请人提供成为脂质代谢和2型DM领域的独立临床研究者所必需的技能。培训目标； 1。在代谢疾病的生物化学中扩大候选人的理论背景。 2。在代谢研究的设计和解释方面获得经验。 3。学习从事代谢研究职业所需的许多实用技术。第二个目标是对L-CPT I在肝脂肪酸代谢中的作用进行新的研究，尤其是与胰岛素抵抗，肝脏脂肪变性和2型DM的发展有关。研究目的：在AIM 1中，我们将检验以下假设：在体外L-CPT I的活性增加将促进脂肪酸氧化，同时还原酰基-COA酯化，细胞内甘油三酸酯（TG）积累和非常低密度的脂蛋白（VLDL）分泌。在AIMS 2、3和4中，CPT I分别在正常大鼠的肝脏，高脂喂养的肥胖/胰岛素耐药大鼠和ZDF肥胖/糖尿病大鼠的肝脏中过表达。升高的肝L-CPT I有望对脂质代谢产生与体外研究所提出的类似作用。我们假设这种改变将减少或防止肝脏中脂质的积累。预计这将是：（1）增强正常大鼠的胰岛素敏感性（AIM 2）；（2）改善与高脂喂养动物中胰岛素抵抗的发展有关的肝脂肪酸代谢的脱离（AIM 3）；（3）防止或扭转伴随ZDF大鼠完全糖尿病表型的脂肪酸代谢异常（AIM 4）。