Scientific Publications Database

Article Title: Associations Between Soluble LDLR and Lipoproteins in a White Cohort and the Effect of PCSK9 Loss-of-Function
Authors: Mayne, Janice; Ooi, Teik Chye; Tepliakova, Lioudmila; Seebun, Deeptee; Walker, Krystal; Mohottalage, Dhanuddara; Ning, Zhibin; Abujrad, Hussein; Mbikay, Majambu; Wassef, Hanny; Chretien, Michel; Figeys, Daniel
Journal: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Volume 103 Issue 9
Date of Publication:2018
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 = -0.307, 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.