OSBPL10, a novel candidate gene for high triglyceride trait in dyslipidemic Finnish subjects, regulates cellular lipid metabolism |
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| Authors: | Julia Perttil? Krista Merikanto Jussi Naukkarinen Ida Surakka Nicolas W. Martin Kimmo Tanhuanp?? Vinciane Grimard Marja-Riitta Taskinen Christoph Thiele Veikko Salomaa Antti Jula Markus Perola Ismo Virtanen Leena Peltonen Vesa M. Olkkonen |
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| Affiliation: | (1) National Institute for Health and Welfare/Public Health Genomics Unit, Biomedicum, P.O. Box 104, 00251 Helsinki, Finland;(2) FIMM, Institute for Molecular Medicine Finland, University of Helsinki, P.O. Box 20, 00014 Helsinki, Finland;(3) Institute of Biomedicine/Anatomy, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland;(4) Queensland Institute of Medical Research, 300 Herston Road, Brisbane, 4029, Australia;(5) Light microscopy Unit, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;(6) Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany;(7) Department of Medicine, Division of Cardiology, Helsinki University Hospital and Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland;(8) Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, 00271 Helsinki, Finland;(9) National Institute for Health and Welfare, 20720 Turku, Finland;(10) Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK;(11) Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland;(12) The Broad Institute, Boston, MA 02142, USA |
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| Abstract: | Analysis of variants in three genes encoding oxysterol-binding protein (OSBP) homologues (OSBPL2, OSBPL9, OSBPL10) in Finnish families with familial low high-density lipoprotein (HDL) levels (N?=?426) or familial combined hyperlipidemia (N?=?684) revealed suggestive linkage of OSBPL10 single-nucleotide polymorphisms (SNPs) with extreme end high triglyceride (TG; >90th percentile) trait. Prompted by this initial finding, we carried out association analysis in a metabolic syndrome subcohort (Genmets) of Health2000 examination survey (N?=?2,138), revealing association of multiple OSBPL10 SNPs with high serum TG levels (>95th percentile). To investigate whether OSBPL10 could be the gene underlying the observed linkage and association, we carried out functional experiments in the human hepatoma cell line Huh7. Silencing of OSBPL10 increased the incorporation of [3H]acetate into cholesterol and both [3H]acetate and [3H]oleate into triglycerides and enhanced the accumulation of secreted apolipoprotein B100 in growth medium, suggesting that the encoded protein ORP10 suppresses hepatic lipogenesis and very-low-density lipoprotein production. ORP10 was shown to associate dynamically with microtubules, consistent with its involvement in intracellular transport or organelle positioning. The data introduces OSBPL10 as a gene whose variation may contribute to high triglyceride levels in dyslipidemic Finnish subjects and provides evidence for ORP10 as a regulator of cellular lipid metabolism. |
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| Keywords: | Cholesterol High-density lipoprotein Microtubule Oxysterol-binding protein Single-nucleotide polymorphism Triglyceride |
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