Fatty acid metabolism and DGAT1 deficiency

脂肪酸代谢和 DGAT1 缺乏

• 批准号: 6891091
• 负责人: Claudio J Villanueva
• 金额: $ 2.89万
• 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/6891091
• 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）：肥胖是II型糖尿病和心脏病的主要致病因素，在美国已达到流行病的程度。肥胖是由于能量输入和输出之间的不平衡造成的，过量的卡路里以甘油三酯的形式储存。缺乏DGAT1（一种参与三酰甘油合成的酶）的小鼠会增加能量消耗，因此具有抗肥胖能力。能量消耗的增加可归因于产热和身体活动的增加。本研究的目的是探讨DGAT1缺乏改变脂肪酸代谢的机制。我假设DGAT1缺乏会减少脂肪酸合成并增加脂肪酸氧化。我的具体目标是：