Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis.
Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis.
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DOI：
10.1038/s41467-021-22167-3
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发表时间：
2021-03-25
影响因子：
16.6
通讯作者：
Zhang DW
中科院分区：
文献类型：
--
作者：
Alabi A;Xia XD;Gu HM;Wang F;Deng SJ;Yang N;Adijiang A;Douglas DN;Kneteman NM;Xue Y;Chen L;Qin S;Wang G;Zhang DW
血浆低密度脂蛋白（LDL）主要由LDL受体（LDLR）清除。LDLR可以被蛋白水解切割以将其可溶性胞外域（sLDLR）释放到细胞外环境中。然而，负责LDLR裂解的蛋白酶是未知的。在这里，我们报告，膜1型基质金属蛋白酶（MT 1-MMP）共免疫沉淀和共定位与LDLR和促进LDLR裂解。在缺乏肝脏MT 1-MMP的小鼠中，血浆sLDLR和胆固醇水平降低，而肝脏LDLR增加。当MT 1-MMP过表达时观察到相反的效果。MT 1-MMP过表达显著增加动脉粥样硬化病变，而MT 1-MMP敲低显著减少载脂蛋白E（apoE）敲除小鼠动脉中胆固醇酯的积累。此外，sLDLR与小鼠和人血浆中含apoB和apoE的脂蛋白相关。在血浆LDL胆固醇水平高的受试者中，sLDLR的血浆水平显著升高。因此，我们证明，MT 1-MMP促进肝LDLR的胞外域脱落，从而调节血浆胆固醇水平和动脉粥样硬化的发展。血浆LDL胆固醇水平升高会增加动脉粥样硬化性心血管疾病的风险。在这里，作者表明，抑制MT 1-MMP降低血浆LDL胆固醇水平和动脉粥样硬化的风险，表明MT 1-MMP抑制作为降脂治疗的潜力。
Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis. Elevated plasma LDL cholesterol levels increase the risk of atherosclerotic cardiovascular disease. Here, the authors show that inhibition of MT1-MMP reduces plasma LDL cholesterol levels and the risk of atherosclerosis, indicating the potential of MT1-MMP inhibition as a lipid-lowering therapy.
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DOI：
10.1016/j.bbamcr.2017.04.015
发表时间：
2017-11
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
--
作者：
Amar S;Smith L;Fields GB
通讯作者：
Fields GB
影响因子：
11.8
作者：
Feinberg TY;Zheng H;Liu R;Wicha MS;Yu SM;Weiss SJ
通讯作者：
Weiss SJ
影响因子：
4.4
作者：
Girona, Josefa;Rodriguez-Borjabad, Celia;Plana, Nuria
通讯作者：
Plana, Nuria
DOI：
10.1016/j.bbalip.2011.07.012
发表时间：
2012-03-01
影响因子：
4.8
作者：
Gao, Xia;Gu, Hongmei;Zhang, Da-wei
通讯作者：
Zhang, Da-wei
影响因子：
11.4
作者：
Koch, S;Strasser, V;Nimpf, J
通讯作者：
Nimpf, J