Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis.

Autor: Alabi A; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Xia XD; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.; Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China., Gu HM; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Wang F; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Deng SJ; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Yang N; Experimental Center for Medical Research, Weifang Medical University, Weifang, China., Adijiang A; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Douglas DN; Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Kneteman NM; Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Xue Y; Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China., Chen L; Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China., Qin S; Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China., Wang G; Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China., Zhang DW; The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. dzhang@ualberta.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Mar 25; Vol. 12 (1), pp. 1889. Date of Electronic Publication: 2021 Mar 25.
DOI: 10.1038/s41467-021-22167-3
Abstrakt: 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.
Databáze: MEDLINE
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