Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake
| Autor: | Daniel S. Greenspan, Kate Fisher, Sreemoti Banerjee, Catherine B. Lawrence, Carolyn D. Jackson, Katherine A. B. Kellett, Christopher J. Duff, Nobuyo Maeda, Nigel M. Hooper, Robert J. Andrew |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Biopsy lcsh:Medicine Q1 Bone Morphogenetic Protein 1 chemistry.chemical_compound Mice 0302 clinical medicine RNA Small Interfering Receptor lcsh:Science Metalloproteinase Oxadiazoles Multidisciplinary medicine.diagnostic_test Chemistry Hep G2 Cells Recombinant Proteins 3. Good health Cell biology Lipoproteins LDL Mechanisms of disease Manchester Institute for Collaborative Research on Ageing Liver Gene Knockdown Techniques lipids (amino acids peptides and proteins) ResearchInstitutes_Networks_Beacons/MICRA Proteolysis Mice Transgenic CHO Cells Bone morphogenetic protein 1 Article 03 medical and health sciences Cricetulus Extracellular medicine Animals Humans Author Correction Dyslipidaemias Cholesterol lcsh:R Atherosclerosis R1 030104 developmental biology Receptors LDL LDL receptor lcsh:Q 030217 neurology & neurosurgery Lipoprotein |
| Zdroj: | Scientific Reports Banerjee, S, Andrew, R J, Duff, C J, Fisher, K, Jackson, C D, Lawrence, C B, Maeda, N, Greenspan, D S, Kellett, K & Hooper, N 2019, ' Proteolysis of the low density lipoprotein receptor by bone morphogenetic protein-1 regulates cellular cholesterol uptake ', Scientific Reports . https://doi.org/10.1038/s41598-019-47814-0 Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-47814-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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