MECHANISMS OF LOW LEVELS OF APOLIPOPROTEIN B

描述：载脂蛋白B水平升高与糖尿病风险增加有关。 冠心病。低β-脂蛋白血症(HBLP)的特征是 载脂蛋白B水平低于5%。申请者已经进行了排序 载脂蛋白B-67、载脂蛋白B-55和载脂蛋白B-44.4截短型突变导致 HBLP，描述了来自与HBLP的Framingham心脏研究的一个亲属，原因是 一个未知的apoB基因突变和纯化的apoB-67 脂蛋白颗粒。杂合子apoB-67患者有一个正常等位基因 产生apoB-100；因此，apoB水平将被预测至少为50 正常的百分比；然而，他们是正常的24%。申请人 已经表明，这些低于预期的水平是由于 极低密度脂蛋白apoB-100、低密度脂蛋白apoB-100和apoB-67的产生增加分解代谢 降低极低密度脂蛋白载脂蛋白B-100，增加从极低密度脂蛋白中直接去除载脂蛋白B-67。这个 申请人提议研究这些观察的机制。特定目标 1定位Framingham家系中apoB基因突变。特定的 目标2是对apoB-55和apoB-44.4进行稳定同位素研究 以确定这些较短截短的载脂蛋白B代谢是否 与apoB-67相似。在具体目标3中，将合成apoB-100 在杂合子apoB-70转基因小鼠中进行研究。如果是25%-25% 正常的窝仔，apoB-100水平降低的机制 将在从转基因小鼠分离的肝细胞中进行研究。在……里面 具体目标4，极低密度脂蛋白的大小和组成将在载脂蛋白B-67中进行比较 用于确定较大尺寸或成分是否发生变化的对象和控件 解释了极低密度脂蛋白apoB-100分解更快的原因。

DESCRIPTION: Elevated apoB levels are associated with an increased risk of coronary heart disease. Hypobetalipoproteinemia (HBLP) is characterized by apoB levels less than the 5 percentile. The applicant has sequenced mutations for truncated forms of apoB-67, apoB-55 and apoB-44.4 which causes HBLP, described a kindred from the Framingham Heart Study with HBLP due to an unidentified apoB gene mutation and purified apoB-67 containing lipoprotein particles. Heterozygous apoB-67 subjects have one normal allele making apoB-100; therefore, apoB levels would be predicted to be at least 50 percent of normal; however, they are 24 percent of normal. The applicant has shown that these lower than expected levels result from decreased production of VLDL apoB-100, LDL apoB-100 and apoB-67, increased catabolism of VLDL apoB-100, and increased direct removal of apoB-67 from VLDL. The applicant proposes to study mechanisms for these observations. Specific aim 1 is to locate the apoB gene mutation in the Framingham kindred. Specific aim 2 is to perform stable isotope studies in the apoB-55 and apoB-44.4 kindreds to determine if apoB metabolism for these shorter truncations is similar to that for apoB-67. In specific aim 3, apoB-100 synthesis will be studied in heterozygous apoB-70 transgenic mice. If it is 25-25 percent of normal litter mates, the mechanism for this reduction in apoB-100 levels will be studied in hepatocytes isolated from the transgenic mice. In specific aim 4, size and composition of VLDL will be compared in apoB-67 subjects and controls to determine if larger size or compositional changes account for the faster catabolism of VLDL apoB-100.