The Role of Apolipoprotein A-V in Chylomicron Metabolism

载脂蛋白A-V在乳糜微粒代谢中的作用 心血管疾病、糖尿病和肥胖是世界范围内的主要临床问题， 甘油三酯（TG）水平构成了这些慢性疾病的独立危险因素。在2001年被发现， 载脂蛋白A-V（apoA-V）是一种由肝脏合成和分泌的蛋白质，其水平与肝脏中的载脂蛋白A-V水平成反比。 与血浆TG水平成比例。与其他载脂蛋白如apoA-IV和apoA-I相比，apoA-V 以极低的浓度循环，这就提出了这样一个问题：如此低的循环载脂蛋白 能对血浆TG产生如此深远的影响。虽然载脂蛋白在脂质代谢中起许多作用， apoA-V降低血浆TG水平的机制尚不清楚。我们的实验室是第一个报告说 apoA-V调节小肠乳糜微粒（CM）的产生和分泌。我们发现：1） apoA-V敲除（KO）小鼠在TG和TG的吸收和淋巴转运方面均显著更好。 2）apoA-V KO小鼠分泌更多的apoB 48（因此具有更多的CM颗粒， 每个颗粒有一个apoB 48）比WT动物分泌到淋巴中; 3）apoA-V在活性脂肪期间分泌到淋巴中 与CM相关的吸收;和4）apoA-V存在于胆汁中，代表apoA-V的第二途径 第一个是流通。在这个建议中，我们将研究1）apoA的重要性- V通过胆汁转运到小肠;和2）载脂蛋白A-V对CM代谢的重要性， 从肠道分泌出来。首先，我们将确定CM的形成和分泌是否受 小肠受来自循环的apoA-V的影响，而不是来自胆汁的apoA-V。第二，我们将确定 apoA-V是否以及如何调节CM的代谢。确切地说，我们将确定apoA-V在 CMs与循环中的apoA-V在CMs代谢中的关系。从拟议研究中获得的信息可能 为我们理解循环apoA-V和血浆TG之间的反比关系提供了新的见解 程度.这项研究不仅新颖，而且还利用了独特的有意识淋巴瘘 小鼠模型开展淋巴瘘小鼠和各种生化和生理研究的培训 将是建立我作为一个生物医学研究员在脂蛋白（特别是CM）和脂质无价 新陈代谢.拟议的研究也可能提供对治疗性治疗的见解， 高血脂症、肥胖症、糖尿病和心血管疾病。假设：ApoA-V是由 肝脏进入胆汁，以调节CM的形成和肠道分泌，以免压倒代谢 肝脏的容量;例如肝切除术后。目的1：由于肝脏是唯一合成 并分泌apoA-V，我们将确定肠道CM的形成和分泌是否受到以下因素的影响： 来自胆汁的apoA-V与来自循环的apoA-V。目的2：确定载脂蛋白A-V是否以及如何调节 CM

The Role of Apolipoprotein A-V in Chylomicron Metabolism Cardiovascular disease, diabetes and obesity are major clinical problems worldwide, and elevated plasma triglyceride (TG) levels constitute an independent risk factor for these chronic disorders. Discovered in 2001, apolipoprotein A-V (apoA-V) is a protein synthesized and secreted by the liver and its levels are inversely proportional to plasma TG levels. Compared with other apolipoproteins, such as apoA-IV and apoA-I, apoA-V circulates at extremely low concentrations, raising the question as to how such a low circulating apolipoprotein can exert such a profound effect on plasma TG. While apolipoproteins serve many roles in lipid metabolism, the mechanism behind apoA-V's ability to lower plasma TG levels is not clear. Our lab was the first to report that apoA-V regulates the production and secretion of chylomicrons (CMs) by the small intestines. We found that: 1) apoA-V knockout (KO) mice are significantly better in the absorption and lymphatic transport of both TG and cholesterol than WT animals; 2) apoA-V KO mice secrete more apoB48 (therefore have more CM particles since there is one apoB48 per particle) into lymph than WT animals; 3) apoA-V is secreted into lymph during active fat absorption associated with CMs; and 4) apoA-V is present in bile, representing a second route of apoA-V transport, with the first being the circulation. In this proposal, we will investigate 1) the importance of apoA- V transport to the small intestine via bile; and 2) the importance of apoA-V on CM metabolism following its secretion from the intestine. First, we will determine whether the formation and secretion of CMs by the small intestines is influenced by apoA-V from the circulation versus that from the bile. Second, we will determine if and how apoA-V regulates the metabolism of CMs. Precisely, we will determine the importance of apoA-V in CMs versus apoA-V in the circulation in the metabolism of CMs. Information from the proposed studies may provide insight to our understanding of the inverse relationship between circulating apoA-V and plasma TG levels. The proposed research is not only novel, but it also takes advantage of the unique conscious lymph fistula mouse model. Training in carrying out lymph fistula mouse and various biochemical and physiological studies will be invaluable in establishing me as a biomedical researcher in lipoprotein (especially CM) and lipid metabolism. The proposed studies may also provide insight into the therapeutic treatment of hypertriglyceridemia, obesity, diabetes and cardiovascular disease. Hypothesis: ApoA-V is secreted by the liver into the bile to regulate CM formation and secretion by the gut so as not to overwhelm the metabolic capacity of the liver; e.g. following hepatectomy. AIM 1: Since the liver is the only organ that synthesizes and secretes apoA-V, we will determine whether the formation and secretion of CM by the gut is influenced by apoA-V from bile versus from circulation. AIM 2: To determine if and how apoA-V regulates the metabolism of CMs.