Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake

Research output: Contribution to journalArticle

  • External authors:
  • Sreemoti Banerjee
  • Robert J. Andrew
  • Christopher J. Duff
  • Kate Fisher
  • Carolyn D. Jackson
  • Nobuyo Maeda
  • Daniel S. Greenspan

Abstract

The development of cardiovascular disease is intimately linked to elevated levels of lowdensity lipoprotein (LDL) cholesterol in the blood. Hepatic LDL receptor (LDLR) levels regulate the amount of plasma LDL. We identified the secreted zinc metalloproteinase, bone morphogenetic protein 1 (BMP1), as responsible for the cleavage of human LDLR within its extracellular ligand-binding repeats at Gly171↓Asp172. The resulting 120 kDa membranebound C-terminal fragment (CTF) of LDLR had reduced capacity to bind LDL and when expressed in LDLR null cells had compromised LDL uptake as compared to the full length receptor. Pharmacological inhibition of BMP1 or siRNA-mediated knockdown prevented the generation of the 120kDa CTF and resulted in an increase in LDL uptake into cells. The 120kDa CTF was detected in the livers from humans and mice expressing human LDLR. Collectively, these results identify that BMP1 regulates cellular LDL uptake and may provide a target to modulate plasma LDL cholesterol.

Bibliographical metadata

Original languageEnglish
JournalScientific Reports
DOIs
Publication statusPublished - 6 Aug 2019

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