A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity

Mahdi M. Motazacker, Juho Pirhonen, Julian C. van Capelleveen, Marion Weber-Boyvat, Jan Albert Kuivenhoven, Saundarya Shah, G. Kees Hovingh, Jari Metso, Shiqian Li, Elina Ikonen, Matti Jauhiainen, Geesje M. Dallinga-Thie, Vesa M. Olkkonen

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Background and aims: Among subjects with high-density-lipoprotein cholesterol (HDL-C) below the 1st percentile in the general population, we identified a heterozygous variant OSBPL1A p.C39X encoding a short truncated protein fragment that co-segregated with low plasma HDL-C.

Methods: We investigated the composition and function of HDL from the carriers and non-carriers and studied the properties of the mutant protein in cultured hepatocytes.

Results: Plasma HDL-C and apolipoprotein (apo) A-I were lower in carriers versus non-carriers, whereas the other analyzed plasma components or HDL parameters did not differ. Sera of the carriers displayed a reduced capacity to act as cholesterol efflux acceptors (p <0.01), whereas the cholesterol acceptor capacity of their isolated HDL was normal. Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I but not to mature HDL particles, suggesting a specific defect in ABCA1-mediated efflux pathway. In hepatic cells, GFP-OSBPL1A partially co-localized in endosomes containing fluorescent apoA-I, suggesting that OSBPL1A may regulate the intracellular handling of apoA-I. The GFP-OSBPL1A-39X mutant protein remained in the cytosol and failed to interact with Rab7, which normally recruits OSBPL1A to late endosomes/lysosomes, suggesting that this mutation represents a loss-of-function.

Conclusions: The present work represents the first characterization of a human OSBPL1A mutation. Our observations provide evidence that a familial loss-of-function mutation in OSBPL1A affects the first step of the reverse cholesterol transport process and associates with a low HDL-C phenotype. This suggests that rare mutations in OSBPL genes may contribute to dyslipidemias. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)140-147
Number of pages8
JournalATHEROSCLEROSIS
Volume249
DOIs
Publication statusPublished - Jun-2016

Keywords

  • Cholesterol efflux
  • High-density lipoprotein
  • Oxysterol-binding protein
  • OSBPL1A
  • Rare variant
  • OXYSTEROL-BINDING-PROTEIN
  • HIGH-DENSITY-LIPOPROTEIN
  • PHOSPHOLIPID TRANSFER PROTEIN
  • CORONARY-HEART-DISEASE
  • CARDIOVASCULAR-DISEASE
  • SENSOR ORP1L
  • HUMANS
  • SERUM
  • RAB7-RILP-P150(GLUED)
  • LOCALIZATION

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