The Role of Apolipoprotein A-V in Chylomicron Metabolism

载脂蛋白A-V在乳糜管代谢中的作用 心血管疾病、糖尿病和肥胖是世界范围内的主要临床问题，血浆水平升高 甘油三酯(TG)水平是这些慢性疾病的独立危险因素。于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，其水平相反 与血浆甘油三酯水平成正比。与其他载脂蛋白如apoA-IV和apoA-I相比，apoA-V 在极低的浓度下循环，提出了这样一个问题，即循环中如此低的载脂蛋白 能对血浆甘油三酯产生如此深远的影响。虽然载脂蛋白在脂肪代谢中起着许多作用，但 载脂蛋白A-V降低血浆甘油三酯水平的机制尚不清楚。我们的实验室是第一个报道 载脂蛋白A-V调节小肠产生和分泌乳糜粒(CMS)。我们发现：1) 载脂蛋白A-V基因敲除(KO)小鼠在甘油三酯和甘油三酯的吸收和淋巴转运方面明显更好 2)apoA-V KO小鼠分泌更多的apoB48(因此有更多的CM颗粒 与WT动物相比，每颗粒有一个apoB48)进入淋巴；3)apoA-V在活跃脂肪期间分泌到淋巴中 与CMS相关的吸收；4)apoA-V存在于胆汁中，代表apoA-V的第二条途径 运输，首先是流通。在这项建议中，我们将调查1)载脂蛋白A的重要性- V通过胆汁转运到小肠；2)载脂蛋白A-V在CM代谢中的重要性 它的分泌物来自肠道。首先，我们将确定CMS的形成和分泌是否由 小肠受到来自循环的载脂蛋白A-V的影响，而不是来自胆汁。第二，我们将确定 载脂蛋白A-V是否以及如何调节细胞质雄性不育症的代谢。准确地说，我们将确定载脂蛋白A-V在 CMS与载脂蛋白A-V在CMS代谢循环中的比较建议研究提供的资料可 有助于我们理解循环载脂蛋白A-V和血浆甘油三酯之间的反向关系 级别。提出的研究不仅新颖，而且还利用了独特的有意识的淋巴瘘。 老鼠模型。淋巴瘘小鼠的训练及各种生化和生理研究 对我成为脂蛋白(尤其是CM)和脂类的生物医学研究人员将是无价的 新陈代谢。拟议中的研究也可能为临床治疗提供洞察。 高甘油三酯血症、肥胖、糖尿病和心血管疾病。假设：载脂蛋白A-V是由 肝脏进入胆汁，调节肠道CM的形成和分泌，以免压倒代谢 肝脏的容量；例如在肝切除后。目标1：因为肝脏是唯一能合成 和分泌载脂蛋白A-V，我们将确定肠道中CM的形成和分泌是否受到 胆汁载脂蛋白A-V与循环载脂蛋白A-V比较。目的2：确定载脂蛋白A-V是否以及如何调节血管紧张素转换酶 不育系CMS。

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.