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危险因素，在美国已达到流行的程度。肥胖是能量输入和输出之间不平衡的结果，其中多余的热量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）的小鼠能量消耗增加，因此具有肥胖抵抗力。能量消耗的增加可归因于生热作用和体力活动的增加。本研究的目的是调查 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： 具体目标 1：确定 Dgatl 4- 小鼠的脂肪酸合成是否减少。 目标 1.1：通过测量氚化水与脂肪酸的结合情况，确定喂食高脂肪饮食的 Dgatl 4- 小鼠肝脏中体内脂肪酸合成是否减少。 目标 1.2：确定 LXR-α 激活的减少（可能是由于不饱和脂肪酸水平增加）是否是脂肪酸合成基因表达减少的原因。 目标 1.3：通过用 LXR-α 激动剂治疗 Dgatl -/- 小鼠，确定 SREBP-1c 表达降低对肥胖抗性表型的贡献。 具体目标 2：确定 Dgatl_- 小鼠的脂肪酸氧化是否增加。 目标 2.1：通过测量 [1-1"C] 棕榈酸酯形成 [1-14C] CO2 并测量酮体的血清水平，确定脂肪酸氧化是否增加。 目标 2.2：确定与脂肪酸氧化相关的基因表达是否增加。 目标 2.3：确定 Dgat1-/- 小鼠的肥胖抵抗表型是否需要 PPAR_（脂肪酸氧化的主要转录调节因子）。