TY - JOUR
T1 - Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease
AU - Vazquez-Chantada, Mercedes
AU - Gonzalez-Lahera, Aintzane
AU - Martinez-Arranz, Ibon
AU - Garcia-Monzon, Carmelo
AU - Regueiro, Manuela M
AU - Garcia-Rodriguez, Juan L
AU - Schlangen, Karin A
AU - Mendibil, Iñaki
AU - Rodriguez-Ezpeleta, Naiara
AU - Lozano, Juan J
AU - Banasik, Karina
AU - Justesen, Johanne M
AU - Jørgensen, Torben
AU - Witte, Daniel R
AU - Lauritzen, Torsten
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Veyrie, Nicolas
AU - Clement, Karine
AU - Tordjman, Joan
AU - Tran, Albert
AU - Le Marchand-Brustel, Yannik
AU - Buque, Xabier
AU - Aspichueta, Patricia
AU - Echevarria-Uraga, Jose J
AU - Martin-Duce, Antonio
AU - Caballeria, Joan
AU - Gual, Philippe
AU - Castro, Azucena
AU - Mato, Jose M
AU - Martinez-Chantar, Maria L
AU - Aransay, Ana M
N1 - Copyright © 2012 American Association for the Study of Liver Diseases.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Diabetes Mellitus, Type 2
KW - Fatty Liver
KW - Female
KW - Gene Frequency
KW - Gene Silencing
KW - Genetic Predisposition to Disease
KW - Glucose Transporter Type 1
KW - Humans
KW - Male
KW - Middle Aged
KW - Oleic Acid
KW - Oxidative Stress
KW - Polymorphism, Single Nucleotide
KW - Transcriptome
U2 - 10.1002/hep.26052
DO - 10.1002/hep.26052
M3 - Journal article
C2 - 22961556
SN - 0270-9139
VL - 57
SP - 505
EP - 514
JO - Hepatology
JF - Hepatology
IS - 2
ER -
