Syndecan-1脱落介导人肝细胞对VLDL结合摄取能力影响的实验研究

发布时间：2017-12-31 05:06

本文关键词：Syndecan-1脱落介导人肝细胞对VLDL结合摄取能力影响的实验研究　出处：《吉林大学》2011年博士论文　论文类型：学位论文

【摘要】：高甘油三脂血症源自血液中富含甘油三酯脂蛋白(TRLs)如乳糜微粒、极低密度脂蛋白(VLDL)的异常累积。机体对TRLs的清除主要是由肝脏内的多种内吞性受体所介导,包括极低密度脂蛋白受体、低密度脂蛋白受体相关蛋白、脂解刺激性脂蛋白受体以及一种或多种硫酸类肝素蛋白聚糖分子(HSPGs)。Syndecan-1是肝细胞表面表达的一类重要HSPG分子,其可在金属蛋白酶的水解作用下从细胞表面脱落,释放荷载有硫酸类肝素糖链的胞外单位。实验室前期研究工作发现,syndecan-1是介导小鼠TRLs肝清除的最重要HSPGs分子。为进一步研究syndecan-1在介导人肝细胞对TRLs清除过程中的作用,本研究以Hep3B细胞及原代正常肝细胞作为模型,通过RNA干扰技术,VLDL结合摄取实验、syndecan-1诱导脱落、建立小鼠动物模型等方法检测了syndecan-1在人肝细胞结合摄取VLDL过程中的作用,阐述了syndecan-1脱落过程的机制及其对人肝细胞结合摄取VLDL的影响。通过研究发现,syndecan-1能够介导人肝细胞对VLDL的结合摄取。Syndecan-1能够在金属蛋白酶的作用下从肝细胞表面自发性或诱导性脱落。ADAM-17是介导PMA诱导syndecan-1从人肝细胞表面脱落的关键酶。PMA诱导肝细胞syndecan-1脱落降低细胞对VLDL的结合摄取能力。脱落的syndecan-1胞外单位能够同VLDL结合,提示体内肝细胞syndecan-1脱落在脂蛋白代谢过程中具有重要生物学意义。LPS注射能够诱导小鼠肝细胞syndecan-1脱落并伴随小鼠血脂水平升高。总之,本实验研究较为系统的阐述了syndecan-1及其脱落过程在人肝细胞对VLDL结合摄取过程中的作用,对于研究高甘油三酯血症的发生机制和治疗方法具有一定指导意义。
[Abstract]:Hypertriglyceridemia is derived from triglyceride-rich triglycerides in the blood, such as chyme particles. TRLs clearance is mediated by a variety of endocytosis receptors in the liver, including very low density lipoprotein receptors (VLDLs). Low density lipoprotein receptor associated protein. Lipoprotein receptor and one or more heparin-like proteoglycan molecules (HSPGsN. Syndecan-1) are important HSPG molecules expressed on the surface of hepatocytes. It can be removed from the cell surface under the hydrolysis of metalloproteinases, and the release load is the extracellular unit of the sulfate heparin sugar chain. Syndecan-1 is the most important HSPGs molecule in murine TRLs liver clearance. In order to further study the role of syndecan-1 in the process of TRLs clearance mediated by human hepatocytes. . In this study, Hep3B cells and primary normal hepatocytes were used as models, and RNA interference technique was used to induce exfoliation of syndecan-1. The role of syndecan-1 in the process of VLDL uptake by human hepatocytes was investigated by establishing animal models in mice. The mechanism of syndecan-1 exfoliation and its effect on VLDL uptake by human hepatocytes were discussed. Syndecan-1 mediates the binding uptake of VLDL by human hepatocytes. Syndecan-1 can spontaneously or inductively exfoliate from the surface of hepatocytes under the action of metalloproteinases. M-17 is the key enzyme of PMA induced syndecan-1 exfoliation from human hepatocytes. PMA-induced syndecan-1 abscission reduces the binding uptake of VLDL by hepatocytes. Ability. Exfoliated syndecan-1 extracellular units can bind to VLDL. The results suggest that syndecan-1 exfoliation of hepatocytes in vivo has important biological significance in lipoprotein metabolism. LPs injection can induce syndecan-1 exfoliation of mouse hepatocytes and accompany with mouse blood. Lipid levels rise. In conclusion, the role of syndecan-1 and its exfoliation in the process of VLDL binding uptake by human hepatocytes was systematically discussed in this study. It is helpful to study the pathogenesis and treatment of hypertriglyceridemia.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R329

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