Article ; Online: Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation.
Biochemical Society transactions
2024 Volume 52, Issue 1, Page(s) 431–440
Abstract: The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well- ... ...
| Abstract | The amount of the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes is the primary determinant of plasma low-density lipoprotein (LDL)-cholesterol level. Although the synthesis and cellular trafficking of the LDLR have been well-documented, there is growing evidence of additional post-translational mechanisms that regulate or fine tune the surface availability of the LDLR, thus modulating its ability to bind and internalise LDL-cholesterol. Proprotein convertase subtilisin/kexin type 9 and the asialoglycoprotein receptor 1 both independently interact with the LDLR and direct it towards the lysosome for degradation. While ubiquitination by the E3 ligase inducible degrader of the LDLR also targets the receptor for lysosomal degradation, ubiquitination of the LDLR by a different E3 ligase, RNF130, redistributes the receptor away from the plasma membrane. The activity of the LDLR is also regulated by proteolysis. Proteolytic cleavage of the transmembrane region of the LDLR by γ-secretase destabilises the receptor, directing it to the lysosome for degradation. Shedding of the extracellular domain of the receptor by membrane-type 1 matrix metalloprotease and cleavage of the receptor in its LDL-binding domain by bone morphogenetic protein-1 reduces the ability of the LDLR to bind and internalise LDL-cholesterol at the cell surface. A better understanding of how the activity of the LDLR is regulated will not only unravel the complex biological mechanisms controlling LDL-cholesterol metabolism but also could help inform the development of alternative pharmacological intervention strategies for the treatment of hypercholesterolaemia. |
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| MeSH term(s) | Receptors, LDL/metabolism ; Cholesterol ; Cholesterol, LDL ; Proteolysis ; Hepatocytes/metabolism ; Ubiquitin-Protein Ligases/metabolism |
| Chemical Substances | Receptors, LDL ; Cholesterol (97C5T2UQ7J) ; Cholesterol, LDL ; Ubiquitin-Protein Ligases (EC 2.3.2.27) |
| Language | English |
| Publishing date | 2024-02-06 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 184237-7 |
| ISSN | 1470-8752 ; 0300-5127 |
| ISSN (online) | 1470-8752 |
| ISSN | 0300-5127 |
| DOI | 10.1042/BST20230918 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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