The LOX-1 receptor ectopically expressed in the liver alleviates atherosclerosis by clearing Ox-LDL from the circulation.
The LOX-1 receptor ectopically expressed in the liver alleviates atherosclerosis by clearing Ox-LDL from the circulation.
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肝脏中异位表达的 LOX-1 受体通过清除循环中的 Ox-LDL 来缓解动脉粥样硬化
DOI：
10.1186/s10020-022-00450-3
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发表时间：
2022-03-02
期刊：
影响因子：
--
通讯作者：
Wei Y
中科院分区：
文献类型：
--
作者：
Wang Z;Chen J;Zeng Z;Zhang Q;Du G;Guo X;Wei Y
氧化型低密度脂蛋白（Ox-LDL）是动脉粥样硬化发生发展的核心因子。然而，几乎没有旨在消除Ox-LDL的疗法。在这项研究中，我们研究了凝集素样氧化低密度脂蛋白受体（LOX-1）在肝脏中的异位表达是否可以导致循环Ox-LDL的消除并阻止其在血管壁中的沉积，从而减轻动脉粥样硬化的进展。AAV 8-TBG-eGFP组（eGFP组）和AAV 8-TBG-LOX-1组（LOX-1组）。LOX-1组小鼠注射病毒稀释液AAV 8-TBG-LOX-1（1.16 × 1011病毒基因组（v.g）/只/100 μl）。对照组和eGFP组的小鼠接受相同量的无菌盐水和AAV 8-TBG-eGFP病毒稀释液注射。采用免疫荧光、免疫印迹和免疫组化方法检测肝组织LOX-1的表达。通过苏木精-伊红（H&E）染色、血液生化分析和免疫荧光法评估病毒的安全性。激光扫描共聚焦显微镜下观察LOX-1与Dil-Ox-LDL的共定位，检测LOX-1在肝脏中的功能。ELISA法检测血浆中Ox-LDL含量。通过血液生化分析评估血脂变化。油红O染色检测动脉粥样硬化病变的进展。免疫荧光染色检测内皮细胞血管细胞粘附分子-1（VCAM-1）的表达及斑块内巨噬细胞的数量和迁移。用qRT-PCR和western blot检测LOX-1在肝脏中的表达。在肝脏中异位表达LOX-1吞噬和降解Ox-LDL，减少循环中的Ox-LDL，但对血脂水平没有显着影响。LOX-1在肝脏表达后，Ox-LDL可被肝细胞清除，从而减少血管内皮VCAM-1的表达和斑块中巨噬细胞的迁移，最终缓解动脉粥样硬化的进展。LOX-1在肝细胞中的功能性表达可能通过上调ATP结合盒G5和G8（ABCG 5/G8）的表达来促进Ox-LDL的代谢清除，ABCG 5/G8是肝胆和经肠胆固醇排泄的主要中性固醇转运体。
ObjectiveOxidized Low-Density-Lipoprotein (Ox-LDL) is the core factor in the development of atherosclerosis. However, there are few therapies aimed at eliminating Ox-LDL. Here in this study, we investigate whether the ectopically expression of the lectin-like oxidized low density lipoprotein receptor (LOX-1) in the liver could lead to the elimination of circulating Ox-LDL and prevent the deposition in the vascular wall, thereby alleviating the progression of atherosclerosis.MethodsApolipoprotein E-deficient (ApoE−/−) mice were randomly divided into three groups, the control group, the AAV8-TBG-eGFP group (eGFP group) and AAV8-TBG-LOX-1 group (LOX-1 group). In the LOX-1 group, mice received an injection of virus dilution AAV8-TBG-LOX-1 (1.16 × 1011virus genome (v.g)/animal/100 μl). The mice in the control group and eGFP group received the same amount of sterile saline and AAV8-TBG-eGFP virus dilution injections. The expression of LOX-1 in the liver was detected by immunofluorescent, western blot and immunohistochemistry. The safety of the virus was assessed by hematoxylin–eosin (H&E) staining, blood biochemical analyses and immunofluorescent. The function of LOX-1 in the liver was detected by the co-localization of LOX-1 and Dil-labeled Ox-LDL (Dil-Ox-LDL) under laser scanning confocal microscope. The extent of Ox-LDL in plasma was detected by ELISA. Changes in blood lipids were assessed through blood biochemical analysis. The progression of atherosclerotic lesions was detected by Oil red O staining. And the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) in endothelial cells and the extent and migration of macrophages in atherosclerotic plaque were detected by immunofluorescence staining. The protein expression in liver was assessed by qRT-PCR and western blot.ResultsThe expression of LOX-1 was stable in liver within 4 weeks. Ectopically expressed LOX-1 in the liver phagocytosed and degraded Ox-LDL and reduced Ox-LDL from circulation but did not have a significant effect on blood lipid levels. After the expression of LOX-1 in liver, Ox-LDL can be cleared by the hepatocytes, thereby reducing VCAM-1 expression in vascular endothelium and the migration of macrophages in plaques, and eventually alleviating the progression of atherosclerosis. Functional expression of LOX-1 in hepatocytes may facilitate the metabolic clearance of Ox-LDL by upregulating the expression of ATP-binding cassette G5 and G8 (ABCG5/G8), which is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion.ConclusionEctopic liver-specific expression of LOX-1 receptor alleviates the progression of atherosclerosis by clearing Ox-LDL from circulation.
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DOI：
10.1016/s0140-6736(18)32203-7
发表时间：
2018-11-10
期刊：
Lancet (London, England)
影响因子：
--
作者：
GBD 2017 Causes of Death Collaborators
通讯作者：
GBD 2017 Causes of Death Collaborators
影响因子：
--
作者：
Julius, Ulrich
通讯作者：
Julius, Ulrich
肾素原受体抑制可重新编程肝脏脂质代谢并保护小鼠免受饮食引起的肥胖和肝脂肪变性
影响因子：
20.1
作者：
Ren L;Sun Y;Lu H;Ye D;Han L;Wang N;Daugherty A;Li F;Wang M;Su F;Tao W;Sun J;Zelcer N;Mullick AE;Danser AHJ;Jiang Y;He Y;Ruan X;Lu X
通讯作者：
Lu X
影响因子：
16.6
作者：
Sassi Y;Avramopoulos P;Ramanujam D;Grüter L;Werfel S;Giosele S;Brunner AD;Esfandyari D;Papadopoulou AS;De Strooper B;Hübner N;Kumarswamy R;Thum T;Yin X;Mayr M;Laggerbauer B;Engelhardt S
通讯作者：
Engelhardt S
通过TAK1介导的磷酸化来调节RIPK1激活，决定了凋亡和坏死性。
影响因子：
16.6
作者：
Geng J;Ito Y;Shi L;Amin P;Chu J;Ouchida AT;Mookhtiar AK;Zhao H;Xu D;Shan B;Najafov A;Gao G;Akira S;Yuan J
通讯作者：
Yuan J