摘要 444：分拣蛋白在 VLDL 分泌中的肝脏特异性作用,Arteriosclerosis, Thrombosis, and Vascular Biology

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摘要 444：分拣蛋白在 VLDL 分泌中的肝脏特异性作用
Arteriosclerosis, Thrombosis, and Vascular Biology ( IF 7.4 ) Pub Date : 2022-03-19 , DOI: 10.1161/atvb.33.suppl_1.a444
Kevin M Patel ₁ , Alanna Strong ₂ , Daniel J Rader ₁

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介绍分拣蛋白是 SORT1 基因的蛋白质产物，是一种多配体分拣受体，参与高尔基体到溶酶体的运输，在多种组织中表达。全基因组关联研究表明，人类肝脏中 SORT1 表达升高与低密度脂蛋白胆固醇 (LDL-C) 和心肌梗死 (MI) 风险降低之间存在关联。我们的实验室此前已表明，小鼠肝脏特异性分拣蛋白过度表达可通过促进 LDL 血浆清除和促进极低密度脂蛋白 (VLDL) 的溶酶体降解来降低 LDL。有趣的是，我们和其他人还发现，小鼠全身 Sort1 缺陷与 VLDL 分泌的反常减少有关（48%，P = 0.004）。一个主要区别是过度表达研究是肝脏特异性的，而功能丧失研究是在全身基因敲除 (KO) 小鼠中进行的。方法/结果我们使用肝脏特异性 Sort1 条件 KO 小鼠和全身 KO 小鼠中肝 Sort1 的重建来进一步探讨肝分拣蛋白在 VLDL 分泌中的具体作用。Sort1 fl/fl 小鼠被注射对照腺相关病毒 (AAV) 或由肝脏特异性启动子驱动的表达 Cre 重组酶的 AAV，并进行体内 VLDL 分泌研究。肝脏特异性 Sort1 缺失使 VLDL 分泌减少 51% (P = 0.005)。我们还使用 AAV 来检验分拣蛋白作为伴侣促进 VLDL 分泌的假设。Sort1 KO 小鼠全身的 Sort1 重建使 VLDL 分泌减少了 29% (P = 0.002)。有趣的是，不能转运至溶酶体但转运至质膜的分拣蛋白突变体的表达使 VLDL 分泌增加了 88%（P = 0.001）。结论这些发现表明，肝脏特异性并不是导致 Sort1 KO 小鼠全身分泌量反常减少的原因，而这种现象在肝脏特异性 sortilin KO 小鼠中也得到了重现。野生型和溶酶体缺陷型分拣蛋白对 VLDL 分泌的不同影响，与分拣蛋白在 VLDL 运输中发挥双重功能的模型一致，低水平的分拣蛋白促进 VLDL 输出，较高水平的分拣蛋白促进分泌前溶酶体 VLDL降解。

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Abstract 444: The Liver-Specific Role of Sortilin in VLDL Secretion

Introduction Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome trafficking that is expressed in multiple tissues. Genome-wide association studies have shown an association between elevated SORT1 expression in human liver and a reduction in low-density lipoprotein cholesterol (LDL-C) and in myocardial infarction (MI) risk. Our lab has previously shown liver specific sortilin overexpression in mice reduces LDL by facilitating LDL plasma clearance and by promoting the lysosomal degradation of very-low density lipoprotein (VLDL). Interestingly, we and others have also shown that total body Sort1 deficiency in mice is associated with a paradoxical reduction in VLDL secretion (48%, P = 0.004). One major difference is that the overexpression studies were hepatic specific whereas the loss-of-function studies were in total body knockout (KO) mice. Methods/Results We used liver-specific Sort1 conditional KO mice and reconstitution of hepatic Sort1 in total body KO mice to further probe the specific role of hepatic sortilin in VLDL secretion. Sort1 fl/fl mice were injected with a control adeno-associated virus (AAV) or an AAV expressing Cre recombinase driven by a liver specific promoter and in vivo VLDL secretion studies were performed. Liver-specific Sort1 deletion reduced VLDL secretion by 51% (P = 0.005). We also used AAV to test the hypothesis that sortilin serves as a chaperone to facilitate VLDL secretion. Sort1 reconstitution in total body Sort1 KO mice reduced VLDL secretion by 29% (P = 0.002). Interestingly, expression of a sortilin mutant that cannot traffic to the lysosome but does traffic to the plasma membrane increased VLDL secretion by 88% (P = 0.001). Conclusion These findings suggest that liver-specificity is not responsible for the paradoxical reduction in secretion seen in the total body Sort1 KO mouse, which is reproduced in the hepatic-specific sortilin KO mouse. The differential effects of wild-type and lysosomal defective sortilin on VLDL secretion and are consistent with a model in which sortilin serves a dual function in VLDL trafficking, with low levels of sortilin facilitating VLDL export and higher levels of sortilin promoting pre-secretory lysosomal VLDL degradation.

更新日期：2022-03-19

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