Adekunle Alabi 1② , GU Hongmei 1 , XIA Xiaodan 1,2 , ZHANG Ziyang 1 , WANG Guiqing 2 ,ZHANG Dawei 1③
(1. Dept. of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, Alberta, Canada, T6G 2R3;2. Dept.of Orthopedics, Qingyuan People′s Hospital of the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan 511518, China)
Abstract Objective: To investigate the effects of membrane type-1 matrix metalloproteinase (MT1-MMP) and γ-secretase or proprotein convertase subtilisin/ kexin type 9 (PCSK9) on the expression of low-density lipoprotein receptor (LDLR). Methods: DsiRNA was used to silence MT1-MMP and PCSK9 expression in cultured human hepatocytes,and the cells were cultured. DAPT was selected to inhibit γ-secretase in cells, and real-time fluorescence quantitative PCR and immunoblotting were used to measure mRNA and protein expression levels, respectively. Results: The combined inhibition of MT1-MMP and γ-secretase or PCSK9 further increased the expression level of LDLR in primary hepatocytes compared with the single inhibition group. The reinfection of PCSK9 -/ - mice with shRNA adeno-associated virus (AAV) targeting MT1-MMP in mice increased the level of LDLR in liver and reduced the concentration of cholesterol in plasma. Conclusion: MT1-MMP and γ-secretase or PCSK9 synergistically regulate LDLR expression. Combined inhibition of MT1-MMP and γ-secretase or PCSK9 has the potential to further increase the expression of LDLR and reduce the level of plasma LDL cholesterol, thereby reducing the risk of cardiovascular disease in patients whose plasma cholesterol levels can not be successfully controlled by currently available strategies.
Keywords: membrane type-1 matrix metalloproteinase; proprotein convertase subtilisin/ kexin type 9; low-density lipoprotein receptor; combined inhibition
DOI:10.19296/ j.cnki.1008-2409.2023-01-003
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