SORTILIN: many headed hydra.
SORTILIN: many headed hydra.
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SORTILIN：多头九头蛇。
DOI：
10.1161/circresaha.115.306036
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发表时间：
2015
影响因子：
20.1
通讯作者：
Tall,AlanR
中科院分区：
文献类型：
--
作者：
Westerterp,Marit;Tall,AlanR
尽管对小鼠巨噬细胞的研究表明 Sort1 会增加动脉粥样硬化，7, 8 对人类的研究表明 SORT1 的较高肝脏表达与 LDL 水平降低有关，尤其是高度促动脉粥样硬化的小 LDL 颗粒。 3 在几种小鼠模型中，对肝脏 SORTILIN 在 LDL 代谢中的作用进行研究，得出了复杂的结果。 3-6, 17-22 虽然 1 项研究表明 SORT1 表达增加似乎会减少 VLDL 分泌并增加肝脏对 LDL 的摄取，4 另一项研究表明 SORTILIN 促进 PCSK9 的分泌，从而降低 LDLR 水平，17 这表明增加肝脏 SORT1 表达会产生相反的作用。然而，人类肝脏 SORT1 表达增加与低密度脂蛋白胆固醇水平降低相关的发现表明，这种机制并不占主导地位。进一步增加复杂性的是，两项独立研究表明，Sort1 完全缺乏会降低 ApoB 和 VLDL 的分泌。 4, 22 在最近的一篇综述中，Strong 等人 18 对 SORT1 过表达和 Sort1 缺陷模型中肝脏 ApoB 分泌减少的原因提供了几种解释，并根据与低水平 Sort1 表达的相关蛋白的类比推测，Adam10 会裂解 SORTILIN 的膜结构域，使管腔片在 VLDL 分泌途径中充当伴侣，从而解释了完全 Sort1 缺陷中 VLDL 分泌的减少（图）。随着 Sort1 表达水平的增加，超过了 Adam10 的能力，因此 SORTILIN 的细胞质尾部被保留，并引导 SORTILIN 与结合的 VLDL 进入溶酶体进行降解。因此，在较高水平的 SORTILIN 下，与中等水平相比，VLDL 分泌也减少。 18 尽管之前的研究表明 SORT1 在肝脏中过度表达可能会导致 LDL 水平降低，但 3、4 增加表达的治疗目标可能难以实现。然而，目前的研究显示 SORTILIN 参与巨噬细胞 LDL 摄取，以及早期发现 Sort1-/- 小鼠已减少 LDL 分泌和 LDL 水平，表明肝脏和巨噬细胞中 ApoB100-SORTILIN 相互作用的完全破坏可能导致 VLDL 分泌和 LDL 水平减少，以及动脉粥样硬化中巨噬细胞对 LDL 的摄取减少。尽管 SORTILIN 可能会降低 LDL 的肝脏清除率，但这会被 VLDL 分泌减少所抵消，并且可以通过伴随的他汀类药物治疗来补偿。总之，尽管在理清 SORTILIN 的复杂性方面已经取得了很大进展，但还需要对人类巨噬细胞和动脉粥样硬化斑块进行更多研究来看看这是否能解释这一点。
Although studies in mouse macrophages suggest that Sort1 increases atherosclerosis, 7, 8 studies in humans have shown that higher hepatic expression of SORT1 is associated with decreased LDL levels, especially highly proatherogenic small LDL particles. 3 Studies on the role of hepatic SORTILIN in LDL metabolism in several mouse models have yielded complex results. 3–6, 17–22 Although 1 study has shown that increased expression of SORT1 seems to decrease VLDL secretion and increase hepatic uptake of LDL, 4 another study showed that SORTILIN facilitates the secretion of PCSK9 and thus reduces LDLR levels, 17 which would suggest the opposite effects of increased hepatic SORT1 expression. However, the finding that increased hepatic SORT1 expression in humans is associated with lower LDL cholesterol levels3 would suggest that this mechanism is not dominant. Further adding to complexity, 2 independent studies have shown that complete Sort1 deficiency decreases ApoB and VLDL secretion. 4, 22 In a recent review, Strong et al18 offer several explanations as to why hepatic ApoB secretion is decreased in both SORT1 overexpression and Sort1 deficiency models and speculated based on analogy with a related protein that at low levels of Sort1 expression, Adam10 cleaves the membrane domain of SORTILIN allowing the luminal piece to act as a chaperone in the secretory pathway of VLDL, thus explaining decreased VLDL secretion in complete Sort1 deficiency (Figure). As Sort1 expression levels increase, the capacity of Adam10 is exceeded and thus the cytoplasmic tail of SORTILIN is retained and directs SORTILIN with bound VLDL toward lysosomes for degradation. Thus, at higher levels of SORTILIN, VLDL secretion is also reduced compared with intermediate levels. 18 Although previous studies have indicated that SORT1 overexpression in the liver might lead to reduced LDL levels, 3, 4 therapeutic targeting to increase expression may be difficult to achieve. However, the present study showing that SORTILIN is involved in macrophage LDL uptake, along with earlier findings showing that Sort1-/-mice have reduced LDL secretion and LDL levels, suggests that complete disruption of the ApoB100-SORTILIN interaction in liver and macrophages might lead to reduced VLDL secretion and LDL levels, as well as reduced uptake of LDL by macrophages in atheromata. Although hepatic clearance of LDL by SORTILIN might be decreased, this would be offset by reduced VLDL secretion and could be compensated by concomitant statin therapy. In sum, although much progress has been made toward sorting out the complexities of SORTILIN, additional studies in human macrophages and atherosclerotic plaques will be needed to see whether this translates.