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 ORCID: https://orcid.org/0000-0002-5373-7546 (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:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	23 Mar 2026 12:30
Last Modified:	18 Jun 2026 20:56
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102555
DOI:	10.1210/jc.2018-00777

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