Original ArticlePlasma inducible degrader of the LDLR, soluble low-density lipoprotein receptor, and proprotein convertase subtilisin/kexin type 9 levels as potential biomarkers of familial hypercholesterolemia in children
Section snippets
Background
Familial hypercholesterolemia (FH) affects 1 of 250 children. FH is under-detected, particularly in pediatric age.1, 2 Gene defects in LDL receptor (LDLR), apolipoprotein B (ApoB), LDLR adaptor protein 1, and proprotein convertase subtilisin/kexin type 9 (PCSK9) are clinically expressed as an FH phenotype.3 The LDLR is the cornerstone molecule regulating the LDL cholesterol (LDL-C) plasma concentrations.4 LDLR gene mutations, leading to a null or defective receptor, result in a substantial
Study design and patients
This study was a cross-sectional study. One hundred seventy-seven children and adolescents, aged 4 to 18 year, who were participating in the “Early Familial Hypercholesterolemia Detection Program in Children” (DECOPIN) to investigate high cholesterol levels or because they were FH family members, were recruited. Children were distributed into 2 groups: (1) familial hypercholesterolemia (FH; n = 77), if they had a positive genetic study or LDL-C > 150 mg/dL if 1 of the parents had FH and (2)
Subject characteristics
The clinical, biochemical, and genetic characteristics of the 177 children (FH = 77; CCh = 100) are shown in Table 1. The median age of the study participants was 10 years. Age, cholesterol, LDL-C, non-high-density lipoprotein cholesterol (HDL-C) and ApoB100 showed significant differences between the groups. Seventy-three percent of FH children were genetically diagnosed. As expected, LDL (total and subclasses) particle number, as assessed by 2-dimensional nuclear magnetic resonance (2D-1
Discussion
We report data on the IDOL, sLDLR, and PCSK9 plasma concentrations in children with FH and controls. Although in the last years the total PCSK9 plasma levels have been exhaustively studied in different metabolic situations, there is only one publication on sLDLR concentrations in healthy subjects17 and this is the first time that the IDOL plasma concentrations have been reported. A wide concentration range of circulating IDOL levels, including patients with undetectable plasma values, was
Acknowledgments
Authors' contributions: All authors acknowledge that he or she participated sufficiently in work to take public responsibility for its content. All authors of this article have read and approved the final version submitted.
This work was jointly supported by national funding from the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Fundació la Marató de TV3 (ref.20152430), Spanish Atherosclerosis Society (SEA), and FEDER funds. The authors acknowledge
References (25)
- et al.
Hipercolesterolemia familiar en la infancia y la adolescencia: una realidad oculta
Clin Investig Arterioscler
(2017) - et al.
PCSK9: a convertase that coordinates LDL catabolism
J Lipid Res
(2009) - et al.
Deubiquitylase inhibition reveals liver X receptor-independent transcriptional regulation of the E3 ubiquitin ligase IDOL and lipoprotein uptake
J Biol Chem
(2016) - et al.
IDOL, inducible degrader of low-density lipoprotein receptor, serves as a potential therapeutic target for dyslipidemia
Med Hypotheses
(2016) - et al.
Liposcale: a novel advanced lipoprotein test based on 2D diffusion-ordered 1H NMR spectroscopy
J Lipid Res
(2015) - et al.
Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders
Clin Investig Arterioscler
(2016) - et al.
Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment
Eur Heart J
(2015) - et al.
Child–parent familial hypercholesterolemia screening in primary care
N Engl J Med
(2016) - et al.
The life cycle of the low-density lipoprotein receptor
Curr Opin Lipidol
(2015) - et al.
LDL-receptor mutations in Europe
Hum Mutat
(2004)
Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk
Circulation
LXR regulates cholesterol uptake through idol-dependent ubiquitination of the LDL receptor
Science
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2022, International Journal of CardiologyCitation Excerpt :Recently, Shimohiro et al documented the association of sLDLR levels with lipoprotein parameters in healthy Japanese adults [20], found that sLDLR is strongly associated with triglycerides (TG). Moreover, Girona et al found significant correlation between sLDLR and TG levels suggesting that it may be a useful biomarker of familial hypercholesterolemia (FH) in children [21]. Not long ago, Mayne et al documented sLDLR level correlate with several lipoprotein parameters, especially TG and the presence of PCSK9 LOF variants alters sLDLR levels and correlations, except for TG.
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2021, Journal of EthnopharmacologyCitation Excerpt :PCSK9 binds to the extracellular domain of LDLR on the cell surface and interferes with recycling of the LDLR back to the cell membrane after endocytosis (Shapiro et al., 2018). Accordingly, strategy to control PCSK9 and LDLR expression have gained attention (Ballantyne et al., 2015) for treatment of hypercholesterolemia (Girona et al., 2018; Zhang et al., 2016). Many naturally-occurring molecules and extracts with PCSK9 regulatory activity have been reported (Adorni et al., 2020; Ahn et al., 2019; Cameron et al., 2008; Chae et al., 2020; Pel et al., 2020).
Inducible degrader of LDLR: A potential novel therapeutic target and emerging treatment for hyperlipidemia
2021, Vascular PharmacologyCitation Excerpt :More importantly, compared to PCSK9, which targets extracellular LDLR in the circulation, IDOL is intracellularly bound to the tail of LDLR, and such intracellular interactions may contribute to the differences observed when inhibitors of IDOL are developed for lipid-lowering therapy [19]. A clinical study revealed that IDOL is present in human blood and is associated with LDL-C levels, but its function and secretory pathway remain unknown [38]. Although this study is interesting, circulating IDOL levels should be further investigated in future studies, especially regarding its source and function.
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The authors have no conflicts of interest relevant to this article to disclose.