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

Adekunle Alabi1, Xiao-Dan Xia1,2, Hong-Mei Gu1

  • 1The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Nature Communications
|March 26, 2021
PubMed

Insights

Membrane type 1-matrix metalloproteinase (MT1-MMP) cleaves the LDL receptor (LDLR), reducing soluble LDLR and plasma cholesterol. This process impacts atherosclerosis development, highlighting MT1-MMP as a key regulator.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Low-density lipoprotein (LDL) clearance is crucial for cholesterol homeostasis, primarily mediated by the LDL receptor (LDLR).
  • The proteolytic processing of LDLR, releasing its soluble ectodomain (sLDLR), and the specific enzyme responsible remain unidentified.
  • Understanding LDLR regulation is vital for managing hypercholesterolemia and atherosclerosis.

Purpose of the Study:

  • To identify the proteinase responsible for the ectodomain shedding of the LDL receptor (LDLR).
  • To investigate the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in LDLR cleavage and its impact on plasma cholesterol levels and atherosclerosis.
  • To elucidate the mechanism by which MT1-MMP influences hepatic LDLR function and lipoprotein metabolism.

Main Methods:

  • Co-immunoprecipitation and co-localization assays to assess the interaction between MT1-MMP and LDLR.
  • In vivo studies using genetically modified mice (MT1-MMP knockout and overexpression models) to evaluate effects on plasma sLDLR, hepatic LDLR, and cholesterol levels.
  • Analysis of atherosclerotic lesions and cholesteryl ester accumulation in apolipoprotein E knockout mice under varying MT1-MMP expression levels.
  • Biochemical assays to measure plasma sLDLR levels and their association with specific lipoproteins.

Main Results:

  • MT1-MMP was identified as the proteinase that cleaves and sheds the LDLR ectodomain.
  • Mice lacking hepatic MT1-MMP exhibited reduced plasma sLDLR and cholesterol, with increased hepatic LDLR.
  • Conversely, MT1-MMP overexpression led to opposite effects on plasma and hepatic LDLR and cholesterol levels.
  • MT1-MMP overexpression exacerbated atherosclerosis, while its knockdown reduced cholesteryl ester accumulation in apoE knockout mice.
  • Plasma sLDLR levels positively correlated with plasma LDL cholesterol in both mouse and human subjects.

Conclusions:

  • MT1-MMP directly promotes the ectodomain shedding of hepatic LDLR.
  • This shedding mechanism plays a significant role in regulating plasma cholesterol levels.
  • MT1-MMP activity is a critical determinant in the development and progression of atherosclerosis.

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