DIETARY OMEGA-3 FATTY ACIDS, GENE EXPRESSION AND GROWTH

膳食 Omega-3 脂肪酸、基因表达和生长

• 批准号: 6011894
• 负责人: William C. Heird
• 金额: $ 29.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6011894
• 关键词: DNA footprinting; acyltransferase; bioenergetics; body weight; chromatin; clinical research; dietary lipid; enzyme activity; gene expression; genetic mapping; genetic transcription; genetic translation; human subject; infant human (0-1 year); laboratory rat; linolenate; lipid metabolism; nutrition related tag; omega 3 fatty acid; oxidized lipid; striated muscles

Dietary omega3 fatty acids have been associated with higher rates of energy expenditure, lower rates of weight gain and/or lower rates of fat deposition in rodents as well as human infants and adults. These fatty acids also have been shown to inhibit transcription of genes encoding rate-limiting enzymes of lipogenesis and to enhance transcription genes encoding rate- limiting enzymes for mitochondrial and peroxisomal oxidation as well as the skeletal muscle content of the putative thermogenic uncoupling protein (UCP)-2. Studies are proposed to determine if the metabolic and genomic events occur in a concerted way in vivo to increase energy expenditure and, hence, decrease rates of fat deposition and weight gain as well as to explore specific cellular and nuclear mechanisms by which the effects of omega3 fatty acids are mediated. Clinical studies, to be conducted in 3-6-month-old infants scheduled for surgical repair of inguinal hernia, will address the hypothesis that omega3 fatty acids regulate gene expression so as to decrease a rate-limiting enzyme of triglyceride synthesis (i.e., glycerol-3-phosphate acyltransferase), increase the rate-limiting enzymes of mitochondrial (i.e., carnitine palmitoyl transferase) and peroxisomal fatty acid oxidation (i.e.,acyl-CoA oxidase) and increase abundance of UCP-2 and/or-3 resulting in greater energy expenditure secondary to the inefficiency of enhanced peroxisomal and/or uncoupled mitochondrial oxidation. Infants will be assigned randomly and blindly to formulas that differ only in alpha-linolenic acid (either 1 percent or 4 percent of total fatty acids) and muscle will be obtained approximately two weeks later, during the scheduled operation, for assay of the mRNA abundance of the cited transcripts. Energy expenditure will be determined at the same time by indirect calorimetry and correlated with mRNA abundances. Studies to be conducted in rats will examine the hypothesis that omega3 fatty acids decrease production of malonyl-CoA, an inhibitor of carnitine palmitoyl transferase, by decreasing expression of and/or inactivating the rate-limiting enzyme for its synthesis, i.e., acetyl-CoA carboxylase. Other studies in rats will utilize DNAse hypersensitivity and in vivo footprinting assays to identify DNA regions in the UCP-2, UCP-3 and acetyl-CoA oxidase genes that are targets for omega3 fatty acid regulation. In toto, the proposed studies will identify molecular and cellular mechanisms by which omega3 fatty acids govern the expression of genes encoding key enzymes of lipid metabolism and the extent to which these effects impact whole body energy expenditure and, hence, rates of fat deposition and weight gain.

膳食ω 3脂肪酸与啮齿类动物以及人类婴儿和成人中较高的能量消耗率、较低的体重增加率和/或较低的脂肪沉积率相关。 这些脂肪酸还显示抑制编码脂肪生成的限速酶的基因的转录，并增强编码线粒体和过氧化物酶体氧化的限速酶以及推定产热解偶联蛋白（UCP）-2的骨骼肌含量的转录基因。 建议进行研究以确定代谢和基因组事件是否以协同的方式在体内发生以增加能量消耗，从而降低脂肪沉积和体重增加的速率，以及探索介导ω 3脂肪酸作用的特定细胞和核机制。 在计划进行腹股沟疝手术修复的3-6个月大婴儿中进行的临床研究将解决ω 3脂肪酸调节基因表达以降低甘油三酯合成的限速酶（即，甘油-3-磷酸酰基转移酶），增加线粒体的限速酶（即，肉毒碱棕榈酰转移酶）和过氧化物酶体脂肪酸氧化（即，酰基-CoA氧化酶）和增加UCP-2和/或-3的丰度，导致更大的能量消耗，继发于增强的过氧化物酶体和/或解偶联线粒体氧化的无效性。 婴儿将被随机盲法分配至仅α-亚麻酸（占总脂肪酸的1%或4%）不同的配方奶粉中，大约两周后，在预定的手术期间，将获得肌肉，用于测定所引用转录物的mRNA丰度。 同时通过间接量热法测定能量消耗，并与mRNA丰度相关。 在大鼠中进行的研究将检验ω 3脂肪酸通过降低其合成的限速酶的表达和/或使其失活来降低丙二酰辅酶A（肉毒碱棕榈酰转移酶的抑制剂）的产生的假设，即，乙酰辅酶A羧化酶 在大鼠中的其他研究将利用DNA酶超敏反应和体内足迹分析来鉴定UCP-2、UCP-3和乙酰辅酶A氧化酶基因中作为ω 3脂肪酸调节靶点的DNA区域。 总的来说，拟议的研究将确定ω 3脂肪酸控制编码脂质代谢关键酶的基因表达的分子和细胞机制，以及这些效应影响全身能量消耗的程度，从而影响脂肪沉积和体重增加的速度。