Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism
Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism
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DOI：
10.1172/jci63563
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Rader, Daniel J.
中科院分区：
文献类型：
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作者：
Strong, Alanna;Ding, Qiurong;Rader, Daniel J.
全基因组关联研究 (GWAS) 发现，染色体 1p13 上的一个基因座存在一个遗传变异，该变异与降低心肌梗塞风险、降低血浆 LDL 胆固醇 (LDL-C) 水平以及显着增加肝脏中 sortilin-1 (SORT1) 基因的表达有关。分拣蛋白是一种溶酶体分选蛋白，它与高尔基体和质膜上的配体结合，并将它们运输到溶酶体。我们之前报道，小鼠肝脏分拣蛋白表达增加可降低血浆 LDL-C 水平。在这里，我们表明，肝分拣蛋白的增加不仅减少了肝载脂蛋白 B (APOB) 的分泌，而且还增加了 LDL 的分解代谢，并且这两种作用都依赖于完整的溶酶体靶向。功能丧失研究表明，分拣蛋白在小鼠体内是 LDL 的真正受体。我们的数据与模型一致，其中增加的肝分拣蛋白与高尔基体中含有 APOB 的细胞内颗粒以及质膜上的细胞外 LDL 结合，并将它们运输到溶酶体进行降解。因此，我们提供了功能性证据，表明基因上增加的肝分拣蛋白表达既减少了肝脏 APOB 分泌，又增加了 LDL 分解代谢，为人类肝分拣蛋白表达增加和血浆 LDL-C 水平降低之间的密切关联提供了双重机制。
Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.