Sort1, Encoded by the Cardiovascular Risk Locus 1p13.3, Is a Regulator of Hepatic Lipoprotein Export
Sort1, Encoded by the Cardiovascular Risk Locus 1p13.3, Is a Regulator of Hepatic Lipoprotein Export
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DOI：
10.1016/j.cmet.2010.08.006
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发表时间：
2010-09-08
期刊：
影响因子：
29
通讯作者：
Nykjaer, Anders
中科院分区：
文献类型：
--
作者：
Kjolby, Mads;Andersen, Olav M.;Nykjaer, Anders
最近的全基因组关联研究显示，高胆固醇血症和心肌梗死与人类染色体1p13.3上的SNPs密切相关。该基因座包括三个基因：SORT1、CELSR2和PSRC1。我们证明了SORT1编码的山梨素是载脂蛋白B100的胞内分选受体。它与高尔基体中的apoB100相互作用，促进含有apoB100的脂蛋白的形成和肝脏输出，从而调节血浆低密度脂蛋白(LDL)胆固醇。在基因靶向的小鼠中，山梨素的缺失减少了肝脏脂蛋白的分泌，并改善了低密度脂蛋白受体缺陷动物的高胆固醇血症和动脉粥样硬化病变的形成。相反，山梨素的过度表达刺激肝脏释放脂蛋白，并增加血浆低密度脂蛋白水平。我们的数据揭示了肝脂蛋白输出的调节途径，并提出了与1p13.3相关的心血管风险的分子解释。
Recent genome-wide association studies (GWAS) have revealed strong association of hypercholesterolemia and myocardial infarction with SNPs on human chromosome 1p13.3. This locus covers three genes: SORT1, CELSR2, and PSRC1. We demonstrate that sortilin, encoded by SORT1, is an intracellular sorting receptor for apolipoprotein (apo) B100. It interacts with apoB100 in the Golgi and facilitates the formation and hepatic export of apoB100-containing lipoproteins, thereby regulating plasma low-density lipoprotein (LDL) cholesterol. Absence of sortilin in gene-targeted mice reduces secretion of lipoproteins from the liver and ameliorates hypercholesterolemia and atherosclerotic lesion formation in LDL receptor-deficient animals. In contrast, sortilin overexpression stimulates hepatic release of lipoproteins and increases plasma LDL levels. Our data have uncovered a regulatory pathway in hepatic lipoprotein export and suggest a molecular explanation for the cardiovascular risk being associated with 1p13.3.