Cargando…
Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia
The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL ex...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Bioscientifica Ltd
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254294/ https://www.ncbi.nlm.nih.gov/pubmed/35560019 http://dx.doi.org/10.1530/EC-22-0019 |
_version_ | 1784740665415958528 |
---|---|
author | Chan, Melody Lok-Yi Shiu, Sammy Wing-Ming Cheung, Ching-Lung Yu-Hung Leung, Anskar Tan, Kathryn Choon-Beng |
author_facet | Chan, Melody Lok-Yi Shiu, Sammy Wing-Ming Cheung, Ching-Lung Yu-Hung Leung, Anskar Tan, Kathryn Choon-Beng |
author_sort | Chan, Melody Lok-Yi |
collection | PubMed |
description | The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9. |
format | Online Article Text |
id | pubmed-9254294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Bioscientifica Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-92542942022-07-05 Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia Chan, Melody Lok-Yi Shiu, Sammy Wing-Ming Cheung, Ching-Lung Yu-Hung Leung, Anskar Tan, Kathryn Choon-Beng Endocr Connect Research The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9. Bioscientifica Ltd 2022-05-13 /pmc/articles/PMC9254294/ /pubmed/35560019 http://dx.doi.org/10.1530/EC-22-0019 Text en © The authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Research Chan, Melody Lok-Yi Shiu, Sammy Wing-Ming Cheung, Ching-Lung Yu-Hung Leung, Anskar Tan, Kathryn Choon-Beng Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title | Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title_full | Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title_fullStr | Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title_full_unstemmed | Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title_short | Effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
title_sort | effects of statins on the inducible degrader of low-density lipoprotein receptor in familial hypercholesterolemia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254294/ https://www.ncbi.nlm.nih.gov/pubmed/35560019 http://dx.doi.org/10.1530/EC-22-0019 |
work_keys_str_mv | AT chanmelodylokyi effectsofstatinsontheinducibledegraderoflowdensitylipoproteinreceptorinfamilialhypercholesterolemia AT shiusammywingming effectsofstatinsontheinducibledegraderoflowdensitylipoproteinreceptorinfamilialhypercholesterolemia AT cheungchinglung effectsofstatinsontheinducibledegraderoflowdensitylipoproteinreceptorinfamilialhypercholesterolemia AT yuhungleunganskar effectsofstatinsontheinducibledegraderoflowdensitylipoproteinreceptorinfamilialhypercholesterolemia AT tankathrynchoonbeng effectsofstatinsontheinducibledegraderoflowdensitylipoproteinreceptorinfamilialhypercholesterolemia |