REGULATION OF INTESTINAL LIPID TRANSPORT

肠道脂质运输的调节

• 批准号: 6176424
• 负责人: CHARLES Milton MANSBACH
• 金额: $ 22.01万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176424
• 关键词: Golgi apparatus; acyl group; apolipoprotein B; apolipoproteins; blood lipoprotein metabolism; chylomicrons; endoplasmic reticulum; fatty acid transport; gastrointestinal absorption /transport; glycerol; high density lipoproteins; intracellular membranes; intracellular transport; laboratory rat; lipid metabolism; lipid transport; lymph; nutrition related tag; phosphatidylcholines; protein binding; triglycerides; vesicle /vacuole

DESCRIPTION: The movement of triacylglycerol (TG) from the intestinal lumen to the lymph in a chylomicron particle is an important function of the intestinal mucosal cell since on metabolism of the chylomicron to produce a chylomicron remnant, HDL is produced as a product. New evidence suggests that remnant production results in the majority of the HDL particles in the plasma. Since HDL is the reverse cholesterol transport particle, the subject of this proposal, which is directed toward understanding the mechanisms by which absorbed TG is directed toward chylomicron formation rather than going directly to the liver via the portal vein, is clinically important. The movement of TG from its site of synthesis in the endoplasmic reticulum (ER) to the Golgi has been an important but unexplored area of research in how TG transits the enterocyte. Recent cell biological studies in the PI's laboratory provide considerable evidence for a unique vesicular transport mechanism for this. The rapidity of movement of TG between the ER and the Golgi correlates with the ability of the intestine to transport TG into the lymph as chylomicrons. Preliminary data show that apolipoprotein AI is present in the ER but not in the transport vesicle. This leads to proposed experiments to define the mechanism by which apoAI does not associate with the developing chylomicron in the ER, and the role of apoAI in the accretion of TG by the cylomicron in the ER. The proteins responsible for the targeting of chylomicrons to the intestinal Golgi in the TG-transport vesicle, the cytosolic protein responsible for enabling fusion of the TG-transport vesicle with the Golgi, and the docking protein on the Golgi that functions to give intestinal Golgi the required binding specificity, will be determined. Studies will also determine the composition of the vesicles, and will determine the flow of TG and apoB-48 from ER to TG-transport vesicle to Golgi. The investigator has found that the intravenous administration of chylomicrons increases the output of TG into the lymph in lymph fistula rats. The second aim of the application is to examine if this is due to the utilization of phosphatidylcholine (PC) from chylomicron remnants for either TG-transport vesicle membrane or chylomicron surface formation. Newly synthesized PC will also be studied for its preferential utilization for TG-transport vesicle membrane or chylomicron surfaces as compared to ER membrane PC. To determine whether PC or apo-B48 drives the TG transport process, studies will also be done in bile fistula, TG-infused and TG+PC-infused rats, to determine if lymph TG output can be dissociated from lymph apoB-48 output.

描述：三酰甘油 (TG) 从肠腔的运动 乳糜微粒中的淋巴液的一个重要功能是 肠粘膜细胞通过乳糜微粒的代谢产生 乳糜微粒残留物，HDL 作为产品生产。 新证据表明 剩余的生产导致大部分 HDL 颗粒 等离子体。 由于 HDL 是胆固醇反向转运颗粒， 本提案的主题旨在理解 吸收的 TG 引导乳糜微粒形成的机制 临床上不是通过门静脉直接进入肝脏 重要的。 TG 在内质网中从其合成位点移动 （ER）对高尔基体的影响一直是一个重要但尚未探索的研究领域 TG 如何转运肠上皮细胞。 PI 最近的细胞生物学研究 实验室为独特的囊泡运输提供了大量证据 为此的机制。 TG 在 ER 和 高尔基体与肠道将 TG 转运至肠道的能力相关 淋巴液为乳糜微粒。 初步数据表明载脂蛋白AI 存在于 ER 中，但不存在于运输囊泡中。 这导致提出的 实验来定义 apoAI 不与 内质网中乳糜微粒的发育以及 apoAI 在增生中的作用 ER 中的 cylomicron 的 TG。 负责的蛋白质 TG 运输中乳糜微粒靶向肠道高尔基体 囊泡，负责实现融合的胞浆蛋白 具有高尔基体的 TG 转运囊泡以及高尔基体上的对接蛋白 其功能是赋予肠道高尔基体所需的结合特异性， 将被确定。 研究还将确定 囊泡，并将确定 TG 和 apoB-48 从 ER 到 TG-转运囊泡至高尔基体。 研究者发现静脉注射 乳糜微粒增加淋巴瘘中 TG 进入淋巴的输出 老鼠。 该应用程序的第二个目的是检查这是否是由于 利用乳糜微粒残余物中的磷脂酰胆碱 (PC) TG-转运囊泡膜或乳糜微粒表面形成。 新 还将研究合成PC的优先利用 TG 转运囊泡膜或乳糜微粒表面与 ER 相比 膜PC。 确定 PC 或 apo-B48 驱动 TG 传输 过程中，还将对胆瘘、TG 输注和 TG+PC输注大鼠，以确定淋巴TG输出是否可以从 淋巴apoB-48输出。