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

J Clin Endocrinol Metab. 2018 Sep 1;103(9):3486-3495. doi: 10.1210/jc.2018-00777.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Canada
  • Cell-Derived Microparticles / genetics
  • Cholesterol, LDL / blood
  • Cross-Sectional Studies
  • European Continental Ancestry Group
  • Female
  • Genotype
  • Humans
  • Lipoproteins / blood*
  • Loss of Function Mutation*
  • Male
  • Middle Aged
  • Proprotein Convertase 9 / blood*
  • Receptors, Cell Surface
  • Receptors, LDL / blood*
  • Triglycerides / blood
  • Young Adult

Substances

  • Cholesterol, LDL
  • LDLR protein, human
  • Lipoproteins
  • Receptors, Cell Surface
  • Receptors, LDL
  • Triglycerides
  • PCSK9 protein, human
  • Proprotein Convertase 9