Hepatic Fatty Acid Metabolism and Insulin Resistance

肝脏脂肪酸代谢和胰岛素抵抗

• 批准号: 7033829
• 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
• 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/7033829
• 关键词: acyl coA; carnitine palmitoyltransferase 1; diabetes mellitus; esterification; fatty acid metabolism; glucose tolerance test; insulin sensitivity /resistance; laboratory rat; liver; liver cells; oxidation; tissue /cell culture; triglycerides; very low density lipoprotein

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和大多数代谢综合征患者中。空腹血浆游离脂肪酸（FFA）在这些受试者中经常升高，并且围绕肝脏FFA氧化在胰岛素抵抗发展中的作用存在重大争议。以前的研究受到缺乏该途径的特异性激活剂的限制。然而，我们的初步数据表明，这个问题可以直接解决的第一次过表达的酶肉毒碱棕榈酰转移酶I（CPT I），一个主要的细胞内调节β-氧化。 这项建议有两个主要目标。首先是为申请人提供成为脂质代谢和2型糖尿病领域独立临床研究者所需的技能。 培训目标; 1.扩展候选人在代谢紊乱的生物化学方面的理论背景。 2.获得代谢研究设计和解释方面的经验。 3.学习许多必要的实用技术，以追求代谢研究事业。 第二个目标是对L-CPT I在肝脏脂肪酸代谢中的作用进行新的研究，特别是因为它与胰岛素抵抗、肝脏脂肪变性和2型糖尿病的发展有关。 研究目的： 在目的1中，我们将检验以下假设：体外肝细胞中L-CPT I活性增加将促进脂肪酸氧化，同时减少酰基辅酶A酯化、细胞内甘油三酯（TG）积累和极低密度脂蛋白（VLDL）分泌。 在目的2、3和4中，CPT I将分别在正常大鼠、高脂肪喂养的肥胖/胰岛素抵抗大鼠和ZDF肥胖/糖尿病大鼠的肝脏中体内过表达。预期肝脏L-CPT I升高对脂质代谢的影响与体外研究中提出的相似。我们假设这种改变将减少或防止肝脏中的脂质积聚。预计这将：（1）增强正常大鼠的胰岛素敏感性（目的2）;（2）改善与高脂喂养动物中胰岛素抵抗的发展相关的肝脏脂肪酸代谢的失调（目的3）;和（3）预防或逆转ZDF大鼠中伴随完全糖尿病表型的脂肪酸代谢异常（目的4）。