Hepatic Fatty Acid Metabolism and Insulin Resistance

肝脏脂肪酸代谢和胰岛素抵抗

• 批准号: 6858733
• 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/6858733
• 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）：