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

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Motazacker , M M , Pirhonen , J , van Capelleveen , J C , Weber-Boyvat , M , Kuivenhoven , J A , Shah , S , Hovingh , G K , Metso , J , Li , S , Ikonen , E , Jauhiainen , M , Dallinga-Thie , G M & Olkkonen , V M 2016 , ' A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity ' , Atherosclerosis , vol. 249 , pp. 140-147 . https://doi.org/10.1016/j.atherosclerosis.2016.04.005

Title: A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity
Author: Motazacker, Mahdi M.; Pirhonen, Juho; van Capelleveen, Julian C.; Weber-Boyvat, Marion; Kuivenhoven, Jan Albert; Shah, Saundarya; Hovingh, G. Kees; Metso, Jari; Li, Shiqian; Ikonen, Elina; Jauhiainen, Matti; Dallinga-Thie, Geesje M.; Olkkonen, Vesa M.
Contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
Date: 2016-06
Language: eng
Number of pages: 8
Belongs to series: Atherosclerosis
ISSN: 0021-9150
URI: http://hdl.handle.net/10138/224029
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.
Subject: 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
3121 General medicine, internal medicine and other clinical medicine
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