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Membrane-type I matrix metalloproteinase (MT1-MMP), lipid metabolism, and therapeutic implications
Xiao-Dan Xia1,2 , Adekunle Alabi2 , Maggie Wang2 , Hong-Mei Gu2 , Rui Zhe Yang2 , Gui-Qing Wang1,* , Da-Wei Zhang2,*
1Department of Orthopedics, The Sixth Affiliated Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511500, China
2Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6R 2G3, Canada
*Correspondence to:Gui-Qing Wang , Email:1918635344@qq.com Da-Wei Zhang , Email:dzhang@ualberta.ca
J Mol Cell Biol, Volume 13, Issue 7, July 2021, Pages 513-526  https://doi.org/10.1093/jmcb/mjab048
Keyword: matrix metalloproteinase, low-density lipoprotein receptor, extracellular matrix, atherosclerosis, cardiovascular disease, obesity

Lipids exert many essential physiological functions, such as serving as a structural component of biological membranes, storing energy, and regulating cell signal transduction. Dysregulation of lipid metabolism can lead to dyslipidemia related to various human diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, lipid metabolism is strictly regulated through multiple mechanisms at different levels, including the extracellular matrix. Membrane-type I matrix metalloproteinase (MT1-MMP), a zinc-dependent endopeptidase, proteolytically cleaves extracellular matrix components, and non-matrix proteins, thereby regulating many physiological and pathophysiological processes. Emerging evidence supports the vital role of MT1-MMP in lipid metabolism. For example, MT1-MMP mediates ectodomain shedding of low-density lipoprotein receptor and increases plasma low-density lipoprotein cholesterol levels and the development of atherosclerosis. It also increases the vulnerability of atherosclerotic plaque by promoting collagen cleavage. Furthermore, it can cleave the extracellular matrix of adipocytes, affecting adipogenesis and the development of obesity. Therefore, the activity of MT1-MMP is strictly regulated by multiple mechanisms, such as autocatalytic cleavage, endocytosis and exocytosis, and post-translational modifications. Here, we summarize the latest advances in MT1-MMP, mainly focusing on its role in lipid metabolism, the molecular mechanisms regulating the function and expression of MT1-MMP, and their pharmacotherapeutic implications.