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

• 批准号: 10300989
• 负责人: Xenia Danae Davis
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-02 至 2022-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300989
• 关键词: Adipose tissue; Animals; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins A; Bile fluid; Biliary; Biochemical; Biomedical Research; Blood; Blood Circulation; Cardiovascular Diseases; Cholesterol; Chronic Disease; Chylomicrons; Clinical; Collection; Conscious; Diabetes Mellitus; Dose; Emulsions; Fatty acid glycerol esters; Fistula; Hepatectomy; Hour; Hydrolysis; Hypertriglyceridemia; Injections; Intestinal Secretions; Intestines; Knock-out; Knockout Mice; Label; Lipids; Lipoproteins; Liquid substance; Liver; Lymph; Lymphatic; Metabolic; Metabolism; Mucous Membrane; Mus; Muscle; Negative Staining; Obesity; Organ; Physiological; Plasma; Production; Proteins; Radioactive; Recombinants; Reporting; Research; Research Personnel; Risk Factors; Role; Route; Sampling; Scintillation Counting; Small Intestines; Spleen; Tail; Therapeutic; Training; Triglycerides; Western Blotting; absorption; apolipoprotein B-48; chylomicron remnant; design; experimental study; insight; knockout animal; lipid metabolism; lymphatic circulation; mouse model; novel; particle; uptake

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.

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，血浆浓度升高 甘油三酯（TG）水平构成这些慢性疾病的独立危险因素。 2001年发现， 载脂蛋白A-V（apoA-V）是由肝脏合成和分泌的蛋白质，其水平成反比 与血浆TG水平成正比。与其他载脂蛋白如apoA-IV和apoA-I相比，apoA-V 载脂蛋白的循环浓度极低，这就提出了这样一个问题：如此低的循环载脂蛋白是如何产生的？ 可以对血浆TG产生如此深远的影响。虽然载脂蛋白在脂质代谢中发挥多种作用， 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道这一情况的 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明显更好 胆固醇水平高于WT动物； 2) apoA-V KO小鼠分泌更多的apoB48（因此有更多的CM颗粒，因为 与 WT 动物相比，每个颗粒有一个 apoB48 进入淋巴液； 3）活性脂肪时apoA-V分泌到淋巴中 与 CM 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。在本提案中，我们将研究 1) apoA- 的重要性 V经胆汁转运至小肠； 2) apoA-V 对 CM 代谢的重要性如下 它是由肠道分泌的。首先，我们将确定CMs的形成和分泌是否通过 小肠受循环中的 apoA-V 与胆汁中的 apoA-V 的影响。其次，我们将确定 apoA-V 是否以及如何调节 CM 的代谢。准确地说，我们将确定 apoA-V 在 CMs 与apoA-V 在CMs 代谢循环中的比较。拟议研究的信息可能 帮助我们了解循环 apoA-V 与血浆 TG 之间的反比关系 水平。所提出的研究不仅新颖，而且还利用了独特的意识淋巴瘘 鼠标模型。进行淋巴瘘小鼠的培训和各种生化和生理学研究 对于我成为脂蛋白（尤其是 CM）和脂质领域的生物医学研究员来说，这将是非常宝贵的 代谢。拟议的研究还可能提供对治疗的见解 高甘油三酯血症、肥胖、糖尿病和心血管疾病。假设：ApoA-V 是由 肝脏进入胆汁以调节肠道的 CM 形成和分泌，以免压倒代谢 肝脏的容量；例如肝切除术后。目标 1：由于肝脏是唯一合成的器官 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。目标 2：确定 apoA-V 是否以及如何调节 CM。