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

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


Abstract

The development of cardiovascular disease is intimately linked to elevated levels of low-density 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 membrane-bound 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 120?kDa CTF and resulted in an increase in LDL uptake into cells. The 120?kDa 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.

Citation

(2019). Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake. Scientific reports, 11416 - ?. https://doi.org/10.1038/s41598-019-47814-0

Acceptance Date Jul 22, 2019
Publication Date Aug 6, 2019
Journal Scientific Reports
Print ISSN 2045-2322
Publisher Nature Publishing Group
Pages 11416 - ?
DOI https://doi.org/10.1038/s41598-019-47814-0
Publisher URL https://doi.org/10.1038/s41598-019-47814-0

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