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

• Published in: Scientific reports Vol. 9; no. 1; p. 11416
• Main Authors: Banerjee, Sreemoti, Andrew, Robert J, Duff, Christopher J, Fisher, Kate, Jackson, Carolyn D, Lawrence, Catherine B, Maeda, Nobuyo, Greenspan, Daniel S, Kellett, Katherine A B, Hooper, Nigel M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 06.08.2019; Nature Publishing Group UK
• Subjects: Animals; Atherosclerosis - blood; Atherosclerosis - drug therapy; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biopsy; Bone density; Bone morphogenetic protein 1; Bone Morphogenetic Protein 1 - antagonists & inhibitors; Bone Morphogenetic Protein 1 - genetics; Bone Morphogenetic Protein 1 - metabolism; Cardiovascular diseases; CHO Cells; Cholesterol; Cricetulus; Gene Knockdown Techniques; Hep G2 Cells; Humans; Lipoproteins, LDL - blood; Lipoproteins, LDL - metabolism; Liver - chemistry; Liver - metabolism; Liver - pathology; Low density lipoprotein; Low density lipoprotein receptors; Metalloproteinase; Mice; Mice, Transgenic; Null cells; Oxadiazoles - pharmacology; Proteolysis; Proteolysis - drug effects; Receptor density; Receptors, LDL - analysis; Receptors, LDL - genetics; Receptors, LDL - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - metabolism; siRNA; Zinc metalloproteinase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47814-0

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 Gly ↓Asp . 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.