The effects of sex and genetics on omega-3 polyunsaturated fatty acid metabolism

性别和遗传对 omega-3 多不饱和脂肪酸代谢的影响

• 批准号: RGPIN-2022-05136
• 负责人: Metherel, Adam
• 金额: $ 2.11万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761550
• 关键词: effects; sex; genetics; omega; polyunsaturated

Eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are omega-3 (n-3) polyunsaturated fatty acids (PUFA) that are high in fish and seafood, the accumulation of which regulates heart and brain function, and fetal/infant growth. However, EPA and DHA in the diets of Canadians is low and we often rely on their synthesis from the nutritionally essential alpha-linolenic acid (ALA, 18:3n-3). Although rates of DHA synthesis from ALA are thought to be low, I have published evidence that may refute this. Methods to assess DHA synthesis rates independent of turnover (i.e. its metabolic consumption to downstream products) are limited. Furthermore, previous animal models of DHA synthesis are not readily translated to humans due to high cost and invasiveness. Females, and in particular pregnant females, have higher DHA levels than males, and this has implications for optimal cardiac/neurological processes and fetal/infant development. Although these sex and pregnancy differences are often attributed to differences in the rates of DHA synthesis, the mechanistic evidence for this is limited as slower turnover of DHA may also explain higher DHA levels. Previously, I have demonstrated that females fed EPA and who had a genetic mutation for an enzyme (elongase 2) involved in the synthesis of DHA, increased DHA levels more than males. However, this and other studies have not been able to properly differentiate between sex differences in DHA synthesis or turnover. Consequently, the long-term objectives of my research program are 1) to develop a novel translational method for the characterization of DHA synthesis and turnover rates, and 2) investigate and understand the mechanisms related to the sex differences in DHA status. I will work towards these long-term goals by focusing on 3 major short-term objectives in the area of sex, pregnancy, genetics and n-3 PUFA metabolism:      1)elucidate differences in DHA synthesis and turnover rates between males and females      2)determine the role of estrogen and elongase 2 on sex differences in DHA metabolism      3)identify the mechanism of increased DHA levels during pregnancy and lactation I will address these goals by performing dietary experiments with mice (female vs. male and pregnancy), estrogen treatments, liver-specific elongase 2 knockout mice and fatty acid analyses for n-3 PUFA levels and carbon-13 abundance. This research will train MSc and BSc students while providing them with valuable research experience and scientific knowledge in the fields of nutrition, metabolism and biochemistry that can be used in a variety of other careers. The results of my research program will provide impactful new insights into the mechanisms explaining sex and pregnancy differences in DHA and n-3 PUFA levels. Understanding the mechanisms to explain higher DHA levels in females will help to provide targeted advice to individuals for improved heart and brain function, and fetal/infant development.

二十碳五烯酸（EPA，20：5 n-3）和二十二碳六烯酸（DHA，22：6 n-3）是ω-3（n-3）多不饱和脂肪酸（PUFA），在鱼类和海鲜中含量较高，其积累可调节心脏和大脑功能以及胎儿/婴儿的生长。然而，加拿大人饮食中的EPA和DHA含量很低，我们通常依赖于从营养必需的α-亚麻酸（ALA，18：3 n-3）中合成它们。尽管人们认为ALA合成DHA的速率很低，但我已经发表了可能反驳这一点的证据。评估DHA合成率独立于周转（即其代谢消耗到下游产品）的方法有限。此外，由于高成本和侵入性，以前的DHA合成动物模型不容易转化为人类。女性，特别是怀孕女性，比男性有更高的DHA水平，这对最佳的心脏/神经过程和胎儿/婴儿发育有影响。虽然这些性别和怀孕差异通常归因于DHA合成速率的差异，但这方面的机械证据有限，因为DHA周转较慢也可以解释较高的DHA水平。以前，我已经证明，女性喂养EPA和谁有一个基因突变的酶（延长酶2）参与DHA的合成，增加DHA水平比男性更多。然而，这项研究和其他研究还不能正确区分DHA合成或周转的性别差异。因此，我的研究计划的长期目标是：1）开发一种新的翻译方法来表征DHA的合成和周转率，2）调查和了解与DHA状态性别差异相关的机制。我将致力于实现这些长期目标，重点关注性、妊娠、遗传学和n-3 PUFA代谢领域的3个主要短期目标： 1）阐明男性和女性之间DHA合成和周转率的差异 2）确定雌激素和延长酶2对DHA代谢性别差异的作用 3）确定怀孕和哺乳期间DHA水平增加的机制我将通过对小鼠（雌性与雄性和怀孕）进行饮食实验、雌激素治疗、肝脏特异性延伸酶2敲除小鼠和对n-3 PUFA水平和碳-13丰度的脂肪酸分析来解决这些目标。这项研究将培养理学硕士和理学士学生，同时为他们提供营养，代谢和生物化学领域的宝贵研究经验和科学知识，可用于各种其他职业。我的研究项目的结果将为解释DHA和n-3 PUFA水平的性别和妊娠差异的机制提供有影响力的新见解。了解女性DHA水平较高的机制将有助于为个人提供有针对性的建议，以改善心脏和大脑功能以及胎儿/婴儿发育。