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Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor
Abstract
Purpose of review The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL and is an important therapeutic target for treating cardiovascular disease. Abundance of the LDLR is subject to both transcriptional and nontranscriptional control. Here, we highlight a new post-transcriptional mechanism for controlling LDLR function via ubiquitination of the receptor by the E3-ubiquitin ligase inducible degrader of the LDLR (IDOL). Recent findings IDOL is a recently identified transcriptional target of the liver X receptors. Acting as an E3-ubiquitin ligase IDOL promotes ubiquitination of the LDLR, thereby marking it for lysosomal degradation. The determinants required for degradation of the LDLR by IDOL have been largely identified. IDOL also targets two related lipoprotein receptors, the very low-density lipoprotein receptor and apolipoprotein E receptor 2. Despite several similarities, the IDOL, and PCSK9 pathways for controlling LDLR abundance seem independent of each other. Genome-wide association studies have recently identified IDOL as a locus influencing variability in circulating levels of LDL, thereby highlighting the possible role of IDOL in human lipoprotein metabolism. Summary Transcriptional induction of IDOL by liver X receptor defines a new post-transcriptional pathway for controlling LDLR abundance and LDL uptake independent of sterol regulatory element binding proteins. Targeting IDOL activity may offer a novel therapeutic…
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IDOL mediates ubiquitination of hepatic LDLR and is a promising therapeutic target for cardiovascular disease.
“Moreover, the inducible degrader of LDLR (IDOL), an E3 ubiquitin ligase that mediates the ubiquitination of hepatic LDLR16,17, has emerged as a promising therapeutic target for cardiovascular disease, similar to PCSK9.”
From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [16]
IDOL and PCSK9 represent major posttranscriptional pathways that promote LDLR degradation, and these pathways represent distinct routes for LDLR degradation.
“IDOL and PCSK9 represent the major posttranscriptional pathways that promote LDLR degradation, and as previously suggested these pathways represent distinct routes for LDLR degradation ( 23, 54 ).”
From The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation (2013) · cites this paper as [23]
IDOL is implicated in lysosomal targeting and degradation of LDLR.
“the E3 ligase IDOL, which has also been implicated in lysosomal targeting and degradation of the LDLR (28,33,34).”
From A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes (2016) · cites this paper as [34]
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Self-citationThe Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL
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Metadata
- Authors
- Sorrentino, V., & Zelcer, N.
- Venue
- Current Opinion in Lipidology
- Published
- 2012-06
- Volume
- 23
- Issue
- 3
- Pages
- 213-219
- ISSN
- 0957-9672
- Cited by
- 55
- References
- 10
- Language
- en
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