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

Adekunle Alabi,Nana Yang,Hong-Mei Gu,Yazhuo Xue,Ayinuer Adijiang,Da-Wei Zhang,Li Chen,Faqi Wang,Guiqing Wang,Shi-Jun Deng,Norman M Kneteman,Donna N Douglas,Shucun Qin,Xiao-Dan Xia

doi:10.1038/s41467-021-22167-3

Abstract

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.

Highlights

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR)
To further confirm the impact of MT1MMP on LDLR expression, we knocked down membrane type 1-matrix metalloproteinase (MT1-MMP) expression in another human hepatoma-derived cell line (HepG2) and found that LDLR levels were significantly increased in MT1-MMP siRNA-transfected cells, whereas the levels of MT2-MMP, LDLR-related protein 1 (LRP-1) and transferrin receptor were comparable in cells transfected with scrambled or MT1-MMP siRNA (Fig. 1c, lanes 2 and 3 vs. 1)
These findings demonstrate that MT1-MMP regulates LDLR expression and LDL uptake in cultured hepatocytes

Summary

Introduction

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. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. We demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis. The ectodomain of LDLR can be cleaved by proteases with the released extracellular domain detected in cell culture media and in human plasma as a soluble form (sLDLR)[10,11,12,13]. Specific knockout of MT1-MMP in mouse hepatocytes increased hepatic LDLR levels and reduced plasma levels of lipoprotein cholesterol. We found that MT1-MMP directly associated with LDLR and promoted its ectodomain cleavage Taken together, these findings demonstrate that hepatic LDLR ectodomain is shed by MT1-MMP and that MT1-MMP regulates plasma LDL-C metabolism and the development of atherosclerosis

Methods

Results

Conclusion