Fatty acid metabolism and DGAT1 deficiency

脂肪酸代谢和 DGAT1 缺乏

• 批准号: 7072713
• 负责人: Claudio J Villanueva
• 金额: $ 2.94万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072713
• 关键词: acyltransferase; bioenergetics; enzyme deficiency; fatty acid biosynthesis; fatty acid metabolism; fatty acids; genetically modified animals; laboratory mouse; obesity; oxidation; peroxisome proliferator activated receptor; predoctoral investigator

DESCRIPTION (provided by applicant): Obesity, a major dsk factor for type II diabetes and heart disease, has reached epidemic proportions in the U.S. Obesity results from an imbalance between energy input and output, where excess calories are stored as triglycerides. Mice lacking DGAT1, an enzyme involved in triacylglycerol synthesis, have increased energy expenditure and are therefore obesity resistant. The increased energy expenditure can be attributed to increased thermogenesis and physical activity. The objectives of this study are to investigate the mechanisms by which DGAT1 deficiency alters fatty acid metabolism. I hypothesize that DGAT1 deficiency decreases fatty acid synthesis and increases fatty acid oxidation. My specific aims are: Specific Aim 1: To determine if fatty acid synthesis is decreased in Dgatl 4- mice. Aim 1.1: Determine if in vivofatty acid synthesis is decreased in livers of Dgatl 4- mice fed a high-fat diet by measuring the incorporation of tritiated water into fatty acids. Aim 1.2: Determine whether decreased activation of LXR-alpha, possibly due to increased levels of unsaturated fatty acids, is responsible for the decreased expression of fatty acid synthesis genes. Aim 1.3: Determine the contribution of decreased expression of SREBP-lc to the obesity-resistance phenotype by treating Dgatl -/- mice with an LXR-alpha agonist. Specific Aim 2: Determine if fatty acid oxidation is increased in Dgatl _- mice. Aim 2.1: Determine if there is increased fatty acid oxidation by measuring the formation of [1-14C] CO2 from [1-1"C] palmitate and measuring the serum levels of ketone bodies. Aim 2.2: Determine if there is increased expression of genes implicated in fatty acid oxidation. Aim 2.3: Determine if PPAR_, a master transcriptional regulator of fatty acid oxidation, is required for the obesity resistance phenotype of Dgat1-/-mice.

描述（由申请人提供）：肥胖症是II型糖尿病和心脏病的主要DSK因子，在美国肥胖症中达到了流行病，这是由于能量输入和输出之间的不平衡而导致的，在该肥胖症中，在该剂量输入和输出之间存在不平衡，在这种情况下，过量卡路里作为甘油三酸酯。缺乏DGAT1的小鼠是一种参与三酰基甘油合成的酶，具有增加的能量消耗，因此具有抗肥胖性。增加的能量消耗可以归因于体力发生和体育活动的增加。这项研究的目标是研究DGAT1缺乏改变脂肪酸代谢的机制。我假设DGAT1缺乏会降低脂肪酸的合成并增加脂肪酸氧化。我的具体目的是： 具体目标1：确定DGATL 4-小鼠中脂肪酸合成是否降低。 AIM 1.1：通过测量将Tritifiated水掺入脂肪酸中，确定喂养高脂饮食的DGATL 4小鼠肝脏中的体内酸合成是否降低。 AIM 1.2：确定LXR-α的激活是否降低，可能是由于不饱和脂肪酸的水平增加，导致脂肪酸合成基因表达降低。 AIM 1.3：通过用LXR-Alpha激动剂处理DGATL - / - 小鼠，确定SREBP-LC表达降低对肥胖表型的贡献。 具体目标2：确定DGATL _-小鼠中脂肪酸氧化是否增加。 AIM 2.1：通过测量[1-14C] partimate的[1-14C] CO2的形成并测量酮体的血清水平来确定脂肪酸氧化增加。 AIM 2.2：确定与脂肪酸氧化有关的基因表达是否增加。 AIM 2.3：确定DGAT1 - / - 小鼠的肥胖抗性表型需要PPAR_是脂肪酸氧化的主转录调节剂。