Rationale: Genome-wide association studies identified single-nucleotide polymorphisms near the SORT1 locus strongly associated with decreased plasma LDL-C (low-density lipoprotein cholesterol) levels and protection from atherosclerotic cardiovascular disease and myocardial infarction. The minor allele of the causal SORT1 single-nucleotide polymorphism locus creates a putative C/EBPα (CCAAT/enhancer-binding protein α)-binding site in the SORT1 promoter, thereby increasing in homozygotes sortilin expression by 12-fold in liver, which is rich in this transcription factor. Our previous studies in mice have showed reductions in plasma LDL-C and its principal protein component, apoB (apolipoprotein B) with increased SORT1 expression, and in vitro studies suggested that sortilin promoted the presecretory lysosomal degradation of apoB associated with the LDL precursor, VLDL (very-low-density lipoprotein).

Objective: To determine directly that SORT1 overexpression results in apoB degradation and to identify the mechanisms by which this reduces apoB and VLDL secretion by the liver, thereby contributing to understanding the clinical phenotype of lower LDL-C levels.

Methods and Results: Pulse-chase studies directly established that SORT1 overexpression results in apoB degradation. As noted above, previous work implicated a role for lysosomes in this degradation. Through in vitro and in vivo studies, we now demonstrate that the sortilin-mediated route of apoB to lysosomes is unconventional and intersects with autophagy. Increased expression of sortilin diverts more apoB away from secretion, with both proteins trafficking to the endosomal compartment in vesicles that fuse with autophagosomes to form amphisomes. The amphisomes then merge with lysosomes. Furthermore, we show that sortilin itself is a regulator of autophagy and that its activity is scaled to the level of apoB synthesis.

Conclusions: These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin and provides a mechanism contributing to the reduced LDL-C found in individuals with SORT1 overexpression.

基本原理：全基因组关联研究确定了SORT1基因座附近的单核苷酸多态性，与血浆LDL-C（低密度脂蛋白胆固醇）水平降低以及动脉粥样硬化性心血管疾病和心肌梗塞的保护作用密切相关。因果SORT1单核苷酸多态性位点的次要等位基因在SORT1启动子中产生一个假定的C /EBPα（CCAAT /增强子结合蛋白α）结合位点，从而使纯合子sortilin在肝脏中的表达增加了12倍，这是富含这种转录因子。我们先前在小鼠中的研究表明，随着SORT1的增加，血浆LDL-C及其主要蛋白成分apoB（载脂蛋白B）减少 表达和体外研究表明，sortilin促进了与LDL前体VLDL（极低密度脂蛋白）相关的apoB在分泌前的溶酶体降解。

目的：直接确定SORT1过表达导致apoB降解，并确定减少肝脏apoB和VLDL分泌的机制，从而有助于了解低LDL-C水平的临床表型。

方法和结果：脉冲追踪研究直接确定SORT1过表达导致apoB降解。如上所述，先前的工作暗示了溶酶体在这种降解中的作用。通过体外和体内研究，我们现在证明，sortilin介导的apoB到溶酶体的途径是非常规的，并且与自噬相交。sortilin的表达增加使更多的apoB远离分泌，这两种蛋白都运输到囊泡中的内体区室，并与自噬体融合形成两亲体。然后，两性体与溶酶体合并。此外，我们表明sortilin本身是自噬的调节剂，其活性被缩放到apoB合成的水平。

结论：这些结果强烈表明，依赖自噬的非常规溶酶体靶向过程可降解apoB，而asortB是由sortilin从分泌途径转移的，并提供了一种机制，可降低SORT1过表达个体的LDL-C含量。