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

二十碳五烯酸(EPA，20：5n-3)和二十二碳六烯酸(DHA，22：6n-3)是鱼类和海产品中含量较高的omega-3(n-3)多不饱和脂肪酸，其积累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，我们经常依赖于它们从营养必需的α-亚麻酸(ALA，18：3n-3)中合成。虽然从丙氨酸合成DHA的速率被认为很低，但我已经发表了可能驳斥这一点的证据。与周转率(即其对下游产品的代谢消耗)无关的DHA合成率的评估方法有限。此外，由于高成本和侵袭性，以前合成DHA的动物模型不容易移植到人类身上。女性，尤其是怀孕的女性，DHA水平高于男性，这对最佳的心脏/神经过程和胎儿/婴儿的发育具有重要意义。虽然这些性别和妊娠差异通常归因于DHA合成速率的差异，但机制证据是有限的，因为DHA周转较慢也可能解释较高的DHA水平。在此之前，我已经证明过，喂食EPA的女性和那些有参与合成DHA的酶(伸长酶2)基因突变的女性，比男性增加的DHA水平更多。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，以及2)调查和了解与DHA状态性别差异相关的机制。我将为实现这些长期目标而努力，重点关注在性、妊娠、遗传学和n-3PUFA代谢领域的3个主要短期目标：1)阐明DHA合成和周转率在男性和女性之间的差异；2)确定雌激素和延伸酶2对DHA代谢中的性别差异的作用；3)确定怀孕和哺乳期DHA水平上升的机制我将通过对小鼠(雌性与雄性和妊娠)进行饮食实验、雌激素治疗、肝脏特异性延伸酶2基因敲除小鼠和n-3PUFA水平和碳13丰度的脂肪酸分析来解决这些目标。这项研究将培训硕士和理科学生，同时为他们提供营养、新陈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性别和怀孕在DHA和n-3 PUFA水平上的差异的机制提供有影响力的新见解。了解女性体内较高的DHA水平的机制将有助于为改善心脏和大脑功能以及胎儿/婴儿发育提供有针对性的建议。

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.