Associations between Soluble LDLR and Lipoproteins in a White Cohort and the Effect of PCSK9 Loss-of-Function

Mayne, Janice, Ooi, Teik Chye, Tepliakova, Lioudmila, Seebun, Deeptee, Walker, Krystal, Mohottalage, Dhanuddara, Ning, Zhibin, Abujrad, Hussein, Mbikay, Majambu, Wassef, Hanny, Chrétien, Michel and Figeys, Daniel (2018) Associations between Soluble LDLR and Lipoproteins in a White Cohort and the Effect of PCSK9 Loss-of-Function. Journal of Clinical Endocrinology and Metabolism, 103 (9). pp. 3486-3495. ISSN 0021-972X

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Abstract

Context: Elevated circulating cholesterol-rich low-density lipoprotein (LDL) particles increase coronary artery disease risk. Cell-surface hepatic LDL receptors (LDLRs) clear 70% of these particles from circulation. The ectodomain of LDLR is shed into circulation, preventing it from removing LDL particles. The role that LDLR ectodomain shedding plays as a regulatory mechanism is unknown.  Objective: We describe LDLR shedding via the relationships between circulating soluble LDLRs (sLDLRs) and serum lipoproteins, serum proprotein convertase subtilin/kexin type 9 (PCSK9; a negative regulator of LDLR), and clinical parameters in a white Canadian population. Design: Population-based, cross-sectional study. Settings: Clinical Research Center, The Ottawa Hospital, and Faculty of Medicine, University of Ottawa.  Participants: Two hundred seventy-three white Canadians.  Intervention: None.  Main Outcome Measures: sLDLR measured by ELISA; serum lipids and PCSK9, PCSK9 genotypes, and clinical parameters from previous analyses.  Results: sLDLRs correlated strongly with triglycerides (TG; r = 0.624, P < 0.0001) and moderately with LDL cholesterol (r = 0.384, P < 0.0001), and high-density lipoprotein cholesterol (r = 20.307, P = 0.0003). Only TG correlations were unaffected by PCSK9 variations. sLDLR levels were significantly elevated in those with TG .50th or LDL cholesterol .75th percentiles.  Conclusions: Serum sLDLR levels correlate with several lipoprotein parameters, especially TG, and the presence of PCSK9 loss-of-function variants alters sLDLR levels and correlations, except for TG. Ectodomain LDLR shedding has a role in LDL metabolism, distinct from PCSK9, with interplay between these two pathways that regulate cell-surface LDLRs. Findings suggest alteration of LDLR shedding could emerge as a target to treat dyslipidemia.

Item Type:	Article
Uncontrolled Keywords:	endocrinology, diabetes and metabolism,biochemistry,endocrinology,clinical biochemistry,biochemistry, medical,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2712
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	23 Mar 2026 12:30
Last Modified:	29 Mar 2026 06:35
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102555
DOI:	10.1210/jc.2018-00777

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