Molecular Form of Dietary DHA and its Bioavailability for the Brain

描述(申请人提供)：DHA(二十二碳六烯酸)是一种omega-3脂肪酸，对大脑的正常功能是绝对必要的，它的不足是已知的。 与几种神经疾病有关，包括阿尔茨海默病(AD)、精神发育迟滞和精神分裂症。虽然大脑在器官中含有最高浓度的DHA，但它无法从前体合成DHA，需要主要从饮食中获得。然而，目前可用的膳食补充剂(鱼油、乙酯、 磷虾油等)在增加大脑DHA水平方面效率低下，尽管它们都很容易用DHA编码其他器官。一个可能的原因是，当所有其他器官以全脂蛋白颗粒的形式摄取DHA时，大脑通过含DHA的脂类通过血脑屏障的分子扩散来摄取DHA，DHA最有效的载体是溶血磷脂酰胆碱(LPC)。因此，血浆磷脂中DHA的存在对其大脑吸收至关重要，因此，膳食中DHA以磷脂的形式而不是三酰甘油(TG)的形式被吸收是非常有利的。然而，目前可用的DHA补充剂都是以TG的形式被吸收的，因为它们中的DHA在胰腺脂肪酶和磷脂酶A2的作用下以游离脂肪酸的形式在肠腔中释放出来，并并入到乳杆菌TG中。在这个探索性项目中，我们将测试这样一个假设，即提供DHA作为磷脂酰胆碱(PC)的sn-1酯将导致其作为磷脂被吸收，因为它逃避了胰腺酶的水解，从而将更有利于大脑的最终吸收。在目标1中，我们将利用体外模型(Caco-2细胞)和体内模型(淋巴瘘大鼠)研究不同分子形式的DHA(游离酸、甘油三酯、PC的sn-1酯、PC的sn-2酯和AS LPC)的吸收。用串联质谱仪和气相色谱测定被吸附的脂类的TG和PC中DHA的相对含量。在目标2中，我们将不同分子形式的DHA作为正常饮食的补充饲喂成年大鼠4周，并测定其在血浆磷脂中的存在以及在肝脏、脂肪组织和脑中的蓄积。如果提出的假设是正确的，DHA在大脑中的累积应该是以PC或LPC的sn-1酯的形式存在于饮食中时最高。这些研究的结果可能导致新的营养疗法，以达到足够的大脑DHA水平，用于健康老龄化和预防神经疾病，如阿尔茨海默病、精神发育迟滞和精神分裂症。

DESCRIPTION (provided by applicant): DHA (docosahexaenoic acid) is an omega-3 fatty acid that is absolutely essential for the normal function of the brain, and its deficiency is known to be associated with several neurological disorders including Alzheimer's disease (AD), mental retardation, and schizophrenia. Although the brain contains the highest concentration of DHA among the organs, it is unable to synthesize DHA from the precursors, and needs to obtain it mostly from the diet. However, the presently available dietary supplements (fish oil, ethyl esters, krill oil, etc.) are inefficient in increasing the brain DHA levels, although they all easily enric the other organs with DHA. One possible reason for this is that while all other organs take up DHA in the form of whole lipoprotein particles, the brain takes it up through molecular diffusion of th DHA-containing lipids through the blood brain barrier, the most efficient carrier of DHA being lysophosphatidylcholine (LPC). Thus, the presence of DHA in plasma phospholipids is crucial for its brain uptake, and consequently, the absorption of dietary DHA in the form of phospholipids, rather than as triacylglycerol (TG), is highly advantageous. However, the presently available supplements of DHA are all absorbed as TG, because DHA in them is released as free fatty acid in the intestinal lumen by the pancreatic lipase and phospholipase A2, and incorporated into chylomicron TG. In this exploratory project, we will test the hypothesis that supplying the DHA as the sn-1 ester of phosphatidylcholine (PC) would result in its absorption as phospholipid because it escapes hydrolysis by the pancreatic enzymes, and thus will be more available for the eventual uptake by the brain. In Aim 1, we will study the absorption of different molecular forms of DHA (free acid, TG, sn-1 ester of PC, sn-2 ester of PC, and as LPC) employing an in vitro model (Caco-2 cells) as well as an in vivo model (lymph fistula rat). The relative amounts of DHA found in TG and PC of the absorbed lipids will be determined by tandem mass spectroscopy and gas chromatography. In Aim 2, we will feed the various molecular forms of DHA as supplements to the normal diets of adult rats for 4 weeks, and determine its appearance in plasma phospholipids, as well as its accumulation in the liver, adipose tissue and brain. If the proposed hypothesis is correct, the accumulation of DHA in the brain should be highest when it is present in the diet as sn-1 ester of PC or LPC. The results from these studies could lead to novel nutraceutical approaches to achieve adequate brain DHA levels for healthy aging and for prevention of neurological diseases such as AD, mental retardation, and schizophrenia.