Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease

Authors

  • Mercedes Vazquez-Chantada,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
    2. OWL Genomics, Derio, Spain
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  • Aintzane Gonzalez-Lahera,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
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  • Ibon Martinez-Arranz,

    1. OWL Genomics, Derio, Spain
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  • Carmelo Garcia-Monzon,

    1. Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, CIBERehd, Madrid, Spain
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  • Manuela M. Regueiro,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
    2. (Present Address) Department of Human and Molecular Genetics, College of Medicine, Florida International University, Miami, FL
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  • Juan L. Garcia-Rodriguez,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
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  • Karin A. Schlangen,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
    2. (Present Address) Max Planck Institute for Molecular Genetics Department of Vertebrate Genomics Research Group, Berlin, Germany
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  • Iñaki Mendibil,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
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  • Naiara Rodriguez-Ezpeleta,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
    2. (Present Address) Marine Research Division, AZTI-Tecnalia, Sukarrieta, Spain
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  • Juan J. Lozano,

    1. Bioinformatics Platform, CIBERehd Hospital Clinic, Centre Esther Koplovitz (CEK), Barcelona, Spain
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  • Karina Banasik,

    1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
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  • Johanne M. Justesen,

    1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
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  • Torben Joergensen,

    1. Research Center for Prevention and Health, Capital Region, Glostrup Hospital, Glostrup, Denmark
    2. Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • Daniel R. Witte,

    1. Steno Diabetes Center, Gentofte, Denmark
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  • Torsten Lauritzen,

    1. Department of Public Health, Section for General Practice, Aarhus University, Aarhus, Denmark
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  • Torben Hansen,

    1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
    2. Hagedorn Research Institute, Gentofte, Denmark
    3. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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  • Oluf Pedersen,

    1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
    2. Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
    3. Hagedorn Research Institute, Gentofte, Denmark
    4. Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
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  • Nicolas Veyrie,

    1. Ambroise Paré Teaching Hospital, Department of General, Digestive and Metabolic Surgery, Université Versailles Saint-Quentin, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
    2. INSERM, U872, Nutriomique, Paris, France; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMR S 872, Paris, France
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  • Karine Clement,

    1. INSERM, U872, Nutriomique, Paris, France; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMR S 872, Paris, France
    2. ICAN Institut Cardiométabolisme et Nutrition, Paris, Pitié-Salpêtrière Hospital, Paris, France
    3. CRNH-Ile de France, Paris, France
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  • Joan Tordjman,

    1. INSERM, U872, Nutriomique, Paris, France; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMR S 872, Paris, France
    2. ICAN Institut Cardiométabolisme et Nutrition, Paris, Pitié-Salpêtrière Hospital, Paris, France
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  • Albert Tran,

    1. INSERM U895, Team 8 “Hepatic Complications of Obesity,” University of Nice, Nice University Hospital, Hepatology Department, Nice, France
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  • Yannik Le Marchand-Brustel,

    1. INSERM U895, Team 8 “Hepatic Complications of Obesity,” University of Nice, Nice University Hospital, Hepatology Department, Nice, France
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  • Xabier Buque,

    1. Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain
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  • Patricia Aspichueta,

    1. Department of Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain
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  • Jose J. Echevarria-Uraga,

    1. Galdakao-Usánsolo Hospital, Galdakao, Spain
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  • Antonio Martin-Duce,

    1. Department of Nursery, Alcalá de Henares University, Madrid, Spain
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  • Joan Caballeria,

    1. Liver Unit, Hospital Clinic, CIBERehd, Barcelona, Spain
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  • Philippe Gual,

    1. INSERM U895, Team 8 “Hepatic Complications of Obesity,” University of Nice, Nice University Hospital, Hepatology Department, Nice, France
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  • Azucena Castro,

    1. OWL Genomics, Derio, Spain
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  • Jose M. Mato,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
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  • Maria L. Martinez-Chantar,

    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
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  • Ana M. Aransay

    Corresponding author
    1. CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
    • Genome Analysis Platform, CIC bioGUNE, CIBERehd, Parque Tecnologico de Bizkaia, Building 801-A, 48160 Derio, Spain
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    • fax: +34 946 568 732


  • Potential conflict of interest: Dr. Witte is an employee of Steno Diabetes Center and owns stock in Novo Nordisk.

  • This research was supported by CYTED 2005-2007 (FIT010000-2005-0013; to A.C. and A.A.M.), La Caixa Foundation 2007-2009 (ID425; to M.L.M.-C. and A.A.M.), Instituto de Salud Carlos III (CIBERehd and PI10/00067; to C.G.-M.) and Fundación Eugenio Rodríguez Pascual (to C.G.-M.); the “Programme Hospitalier de Recherche Clinique” Assistance Publique-Hôpitaux de Paris (AOR 02076), the Commission of the European Communities (Collaborative Project “Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome” HEPADIP, contract LSHM-CT-2005-018734), the European Union Seventh Framework Program (FP7/2007-2013, under grant agreement no. Health-F2-2009-241762, for the project FLIP), the Department of Industry, Tourism, and Trade of the Government of the Autonomous Community of the Basque Country, Saiotek research program (S-PE09UN28 and SA-2010/0025; to X.B. and P.A.); and the Department of Education of the Government of the Autonomous Community of the Basque Country (IT-336-10; to X.B. and P.A.) projects. CIC bioGUNE support was provided from The Department of Industry, Tourism, and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2005-2007) and from the Innovation Technology Department of the Bizkaia County. The Danish part of the study was supported by grants from the Lundbeck Foundation Center for Applied Medical Genomics in Personalized Disease Prediction, Prevention, and Care (www.LuCAMP.org) and from “Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome” (HEPADIP; www.hepadip.org), which is supported by the European Commission as an integrated project under the 6th Framework Program (LSHM-CT-2005-018734). The Basque Biobank is supported by the Basque Foundation for Health Innovation and Research.

Abstract

Susceptibility to develop nonalcoholic fatty liver disease (NAFLD) has genetic bases, but the associated variants are uncertain. The aim of the present study was to identify genetic variants that could help to prognose and further understand the genetics and development of NAFLD. Allele frequencies of 3,072 single-nucleotide polymorphisms (SNPs) in 92 genes were characterized in 69 NAFLD patients and 217 healthy individuals. The markers that showed significant allele-frequency differences in the pilot groups were subsequently studied in 451 NAFLD patients and 304 healthy controls. Besides this, 4,414 type 2 diabetes mellitus (T2DM) cases and 4,567 controls were genotyped. Liver expression of the associated gene was measured and the effect of its potential role was studied by silencing the gene in vitro. Whole genome expression, oxidative stress (OS), and the consequences of oleic acid (OA)-enriched medium on lipid accumulation in siSLC2A1-THLE2 cells were studied by gene-expression analysis, dihydroethidium staining, BODIPY, and quantification of intracellular triglyceride content, respectively. Several SNPs of SLC2A1 (solute carrier family 2 [facilitated glucose transporter] member 1) showed association with NAFLD, but not with T2DM, being the haplotype containing the minor allele of SLC2A1 sequence related to the susceptibility to develop NAFLD. Gene-expression analysis demonstrated a significant down-regulation of SLC2A1 in NAFLD livers. Enrichment functional analyses of transcriptome profiles drove us to demonstrate that in vitro silencing of SLC2A1 induces an increased OS activity and a higher lipid accumulation under OA treatment. Conclusions: Genetic variants of SLC2A1 are associated with NAFLD, and in vitro down-regulation of this gene promotes lipid accumulation. Moreover, the oxidative response detected in siSLC2A1-THLE2 cells corroborated the antioxidant properties previously related to this gene and linked the most representative clinical characteristics of NAFLD patients: oxidative injury and increased lipid storage. (HEPATOLOGY 2013)

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