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首页> 外文学位 >The Effect of Single Nucleotide Polymorphisms in Apolipoprotein(a) KIV Types 6-9 on Lipoprotein(a) Particle Assembly and Apolipoprotein(a) Secretion In Vitro
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The Effect of Single Nucleotide Polymorphisms in Apolipoprotein(a) KIV Types 6-9 on Lipoprotein(a) Particle Assembly and Apolipoprotein(a) Secretion In Vitro

机译：载脂蛋白（a）KIV 6-9型单核苷酸多态性对脂蛋白（a）颗粒装配和载脂蛋白（a）体外分泌的影响

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摘要

Elevated plasma levels of lipoprotein(a) (Lp(a)) is considered to be the strongest genetic risk factor for cardiovascular diseases (CVDs). Lp(a) is similar in composition to low density lipoprotein (LDL), but is distinguishable by its unique polymorphic glycoprotein, apolipoprotein(a) (apo(a)). Lp(a) plasma levels are primarily determined by allelic variations in the gene that encodes apo(a). Rate of apo(a) secretion from hepatocytes and the efficiency of Lp(a) assembly influences plasma levels. Lp(a) is assembled by a non-covalent interaction between its two components, that precedes formation of a single disulfide bond between apo(a) and apolipoproteinB-100 (apoB-100) of the LDL moiety. Single nucleotide polymorphisms (SNPs) identified in the apo(a) domains that are implicated in this two-step assembly process have been associated with plasma Lp(a) levels. G17R, P52L, S37F, and T23P, have been associated with decreased Lp(a) levels, whereas R18W has been associated with increased levels. The work in this study uses site-directed mutagenesis to introduce the aforementioned SNPs into a physiologically relevant 17K apo(a) isoform to establish potential causation for the observed associative Lp(a) levels followed by in vitro assays of Lp(a) formation. Pulse-chase experiments in transiently transfected human hepatoma cells (HepG2) with mutants and wildtype (WT) 17K apo(a) was used to study the secretion of apo(a) variants and a recombinant Lp(a) assay with purified components was used to study the assembly of Lp(a). Computational chemistry was used to determine conformational changes introduced by the SNPs in their respective apo(a) domains. Interpretation of the presented data suggests that R18W enhances the rate of covalent Lp(a) assembly and P52L decreases efficiency of covalent Lp(a) assembly. S37F, G17R, and T23P, did not present data that correlated to their effects on human Lp(a) plasma concentration.
机译：血浆脂蛋白（a）（Lp（a））水平升高被认为是心血管疾病（CVD）的最强遗传危险因素。 Lp（a）的成分与低密度脂蛋白（LDL）相似，但可以通过其独特的多形糖蛋白载脂蛋白（a）（apo（a））加以区分。 Lp（a）血浆水平主要由编码apo（a）的基因的等位基因变异决定。肝细胞分泌apo（a）的速率和Lp（a）装配的效率影响血浆水平。 Lp（a）通过其两个组件之间的非共价相互作用组装而成，该相互作用在LDL部分的apo（a）和载脂蛋白B-100（apoB-100）之间形成单个二硫键之前。在此两步组装过程中涉及的apo（a）域中鉴定出的单核苷酸多态性（SNP）已与血浆Lp（a）水平相关。 G17R，P52L，S37F和T23P与Lp（a）水平降低有关，而R18W与水平Lp（a）相关。这项研究中的工作使用定点诱变将上述SNP引入生理相关的17K apo（a）同工型，以建立观察到的相关Lp（a）水平的潜在因果，然后进行Lp（a）形成的体外测定。在具有突变体和野生型（WT）17K apo（a）的瞬时转染的人肝癌细胞（HepG2）中进行脉冲追踪实验，以研究apo（a）变体的分泌，并使用具有纯化成分的重组Lp（a）分析研究Lp（a）的组装。计算化学用于确定SNP在其各自的apo（a）域中引入的构象变化。所提供数据的解释表明，R18W提高了共价Lp（a）组装的速率，而P52L降低了共价Lp（a）组装的效率。 S37F，G17R和T23P没有提供与其对人Lp（a）血浆浓度的影响相关的数据。

著录项

  • 作者

    Sayegh, Sera.;

  • 作者单位

    University of Windsor (Canada).;

  • 授予单位 University of Windsor (Canada).;
  • 学科 Biochemistry.;Computational chemistry.;Molecular biology.
  • 学位 M.Sc.
  • 年度 2018
  • 页码 117 p.
  • 总页数 117
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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