title: Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease.
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.
authors.affiliation: CIC bioGUNE, Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Vazquez-Chantada
authors.forename: Aintzane
authors.initials: A
authors.lastname: Gonzalez-Lahera
authors.forename: Ibon
authors.initials: I
authors.lastname: Martinez-Arranz
authors.forename: Carmelo
authors.initials: C
authors.lastname: Garcia-Monzon
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Regueiro
authors.forename: Juan L
authors.initials: JL
authors.lastname: Garcia-Rodriguez
authors.forename: Karin A
authors.initials: KA
authors.lastname: Schlangen
authors.forename: Iñaki
authors.initials: I
authors.lastname: Mendibil
authors.forename: Naiara
authors.initials: N
authors.lastname: Rodriguez-Ezpeleta
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Justesen
authors.forename: Torben
authors.initials: T
authors.lastname: Joergensen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Witte
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veyrie
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Joan
authors.initials: J
authors.lastname: Tordjman
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.forename: Yannik
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Xabier
authors.initials: X
authors.lastname: Buque
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Echevarria-Uraga
authors.forename: Antonio
authors.initials: A
authors.lastname: Martin-Duce
authors.forename: Joan
authors.initials: J
authors.lastname: Caballeria
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.forename: Azucena
authors.initials: A
authors.lastname: Castro
authors.forename: Jose M
authors.initials: JM
authors.lastname: Mato
authors.forename: Maria L
authors.initials: ML
authors.lastname: Martinez-Chantar
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D019301:Oleic Acid / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D059467:Transcriptome
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D019301:Oleic Acid