Sex Differences in Fatty Acid Metabolism

女性和男性血液和组织中的脂肪酸是不同的。本研究的长期目标是确定导致哺乳动物体内二十二碳六烯酸（DHA）（一种omega-3多不饱和脂肪酸）水平不同的脂肪酸代谢的性别差异，以及n-7和n-9单不饱和脂肪酸水平的差异。我们将研究控制脂肪酸水平的各种因素，包括脂肪酸合成、脂肪酸与复合脂质的结合、脂肪酸氧化和饮食。在啮齿类动物模型中，我们观察到参与这些脂肪酸合成的基因表达的性别差异。这似乎是由雌激素的直接作用调节的，但也间接影响一般的脂肪生成。因此，除了性激素对脂肪酸合成的影响外，我们还将使用脂质分析和基因表达筛选技术（霰弹枪脂质组学和基因微阵列）来确定啮齿动物代谢途径的性别差异。特别是，我们将研究雌激素在细胞膜磷脂合成中的作用，以及用于能量储存的三酰基甘油的合成。我们预计脂肪酸合成的性别差异主要发生在肝脏，雌激素介导了几种参与脂质合成的转录因子，包括固醇调节元件结合蛋白-1c、过氧化物酶体增殖体激活受体、肝脏X受体和碳水化合物反应元件结合蛋白。我们还希望在关键酶如delta-6去饱和酶的启动子区域发现雌激素反应元件。从这项研究中获得的理解可以为人类和动物生理各系统的性别差异以及脂肪酸的摄取和结合提供见解。例如，n-7单不饱和脂肪酸代谢的性别差异可能部分解释了胰岛素敏感性的性别差异。更好地了解n-3多不饱和脂肪酸的代谢和生物合成对于确定人类的营养需求和帮助制定增加食物中n-3多不饱和脂肪酸的策略至关重要。

Fatty acids in blood and tissues are different in women and men. The long term objective of the present research is to determine the sex differences in fatty acid metabolism that result in different levels of docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acids and differences in levels of n-7 and n-9 monounsaturated fatty acids in mammals. We will examine various factors that control the levels of fatty acids including fatty acid synthesis, fatty acid incorporation into complex lipids, fatty acid oxidation, and diet. In rodent models, we have observed sex differences in the expression of genes involved in the synthesis of these fatty acids. This appears to be regulated by a direct effect of estrogen, but also indirect effects on general lipogenesis. Therefore, in addition to sex hormone effects on fatty acid synthesis, we will use lipid analytical and gene expression screening techniques (shot-gun lipidomics and gene microarrays) to identify sex differences in metabolic pathways in rodents. In particular, we will be examining the role of estrogen on the synthesis of phospholipids for cell membranes, and the synthesis of triacylglycerols for energy storage. We expect that the sex differences in fatty acid synthesis mainly occur in the liver and that estrogen is mediates several transcription factors involved in lipid synthesis including sterol regulatory element binding protein-1c, peroxisome proliferator activated receptors, liver X receptor, and carbohydrate responsive element binding protein. We also expect to discover estrogen response elements in the promoter regions of key enzymes such as delta-6 desaturase. The understanding gained from this research can provide insight on sex differences in various systems in human and animal physiology and on fatty acid uptake and incorporation. For example, sex differences in n-7 monounsaturated fatty acids metabolism may partially explain sex differences in insulin sensitivity. A greater understanding of the metabolism and biosynthesis of n-3 polyunsaturated fatty acids is critical to determine nutritional requirements in humans, and to assist in strategies to increase n-3 polyunsaturated fatty acids in the food supply.