PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9
PAQR3 modulates blood cholesterol level by facilitating interaction between LDLR and PCSK9
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PAQR3 通过促进 LDLR 和 PCSK9 之间的相互作用来调节血液胆固醇水平
DOI：
10.1016/j.metabol.2019.02.005
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发表时间：
2019-05-01
影响因子：
9.8
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Huang, Meiqin;Zhao, Zilong;Chen, Yan
目的：低密度脂蛋白胆固醇（LDL-C）是动脉粥样硬化性心血管疾病的标志。肝脏LDL受体（LDLR）在循环LDL-C的清除中起重要作用。PCSK 9促进溶酶体中LDLR的降解，并且拮抗PCSK 9已成功地用于临床以降低血液LDL-C水平。在这里，我们确定了一个新的球员，调节LDLR与PCSK 9的相互作用，从而控制LDLR降解和胆固醇homeostasis.Methods：血液LDL-C和胆固醇水平进行了分析，在肝脏缺失Paqr 3基因的小鼠。在HepG 2细胞中分析LDLR的半衰期。结果：Paqr 3基因缺失小鼠经高脂饲料喂养后，血LDL-C和总胆固醇水平均显著低于对照组（p < 0.001和p < 0.05）。LDLR蛋白的稳态水平因Paqr 3敲低/缺失而升高，因PAQR 3过表达而降低。LDLR蛋白的半衰期通过Paqr 3敲低而增加，并通过PAQR 3过表达而加速。PAQR 3分别与LDLR的β折叠结构域和PCSK 9的P结构域相互作用。此外，PAQR 3可以定位于早期内体中，并与LDLR、PCSK 9和LDL共定位。从机制上讲，PAQR 3增强了LDLR与PCSK 9之间的相互作用。结论：我们的研究表明，PAQR 3通过调节LDLR与PCSK 9的相互作用，在控制肝脏LDLR降解和血液LDL-C水平方面发挥着关键作用。(C)2019爱思唯尔公司All rights reserved.
Objective: Low-density lipoprotein cholesterol (LDL-C) is the hallmark of atherosclerotic cardiovascular diseases. The hepatic LDL receptor (LDLR) plays an important role in clearance of circulating LDL-C. PCSK9 facilitates degradation of LDLR in the lysosome and antagonizing PCSK9 has been successfully used in the clinic to reduce blood LDL-C level. Here we identify a new player that modulates LDLR interaction with PCSK9, thus controlling LDLR degradation and cholesterol homeostasis.Methods: The blood LDL-C and cholesterol levels were analyzed in mice with hepatic deletion of Paqr3 gene. The half-life of LDLR was analyzed in HepG2 cells. The interaction of PAQR3 with LDLR and PCSK9 was analyzed by co-immunoprecipitation and immunofluorescent staining.Results: The blood LDL-C and total cholesterol levels in the mice with hepatic deletion of Paqr3 gene were significantly lower than the control mice after feeding with high-fat diet (p < 0.001 and p < 0.05 respectively). The steady-state level of LDLR protein is elevated by Paqr3 knockdown/deletion and reduced by PAQR3 overexpression. The half-life of LDLR protein is increased by Paqr3 knockdown and accelerated by PAQR3 overexpression. PAQR3 interacts with the beta-sheet domain of LDLR and the P-domain of PCSK9 respectively. In addition, PAQR3 can be localized in early endosomes and colocalized with LDLR, PCSK9 and LDL. Mechanistically, PAQR3 enhances the interaction between LDLR and PCSK9.Conclusion: Our study reveals that PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction. (C) 2019 Elsevier Inc. All rights reserved.