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

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.

SUBMITTER: Banerjee S

PROVIDER: S-EPMC6684651 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Banerjee Sreemoti S Andrew Robert J RJ Duff Christopher J CJ Fisher Kate K Jackson Carolyn D CD Lawrence Catherine B CB Maeda Nobuyo N Greenspan Daniel S DS Kellett Katherine A B KAB Hooper Nigel M NM

Scientific reports 20190806 1

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<sub>171</sub>↓Asp<sub>172</sub>. The resulting 120 kDa membrane-bound C-terminal fragment (CTF) of L ...[more]

PMID: 31388055

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Dataset Information

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

Publications

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

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