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

Mercedes Vazquez-Chantada; Aintzane Gonzalez-Lahera; Ibon Martinez-Arranz; Carmelo Garcia-Monzon; Manuela M Regueiro; Juan L Garcia-Rodriguez; Karin A Schlangen; Iñaki Mendibil; Naiara Rodriguez-Ezpeleta; Juan J Lozano; Karina Banasik; Johanne M Justesen; Torben Jørgensen; Daniel R Witte; Torsten Lauritzen; Torben Hansen; Oluf Pedersen; Nicolas Veyrie; Karine Clement; Joan Tordjman; Albert Tran; Yannik Le Marchand-Brustel; Xabier Buque; Patricia Aspichueta; Jose J Echevarria-Uraga; Antonio Martin-Duce; Joan Caballeria; Philippe Gual; Azucena Castro; Jose M Mato; Maria L Martinez-Chantar; Ana M Aransay

doi:10.1002/hep.26052

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

Mercedes Vazquez-Chantada, Aintzane Gonzalez-Lahera, Ibon Martinez-Arranz, Carmelo Garcia-Monzon, Manuela M Regueiro, Juan L Garcia-Rodriguez, Karin A Schlangen, Iñaki Mendibil, Naiara Rodriguez-Ezpeleta, Juan J Lozano, Karina Banasik, Johanne M Justesen, Torben Jørgensen, Daniel R Witte, Torsten Lauritzen, Torben Hansen, Oluf Pedersen, Nicolas Veyrie, Karine Clement, Joan TordjmanAlbert Tran, Yannik Le Marchand-Brustel, Xabier Buque, Patricia Aspichueta, Jose J Echevarria-Uraga, Antonio Martin-Duce, Joan Caballeria, Philippe Gual, Azucena Castro, Jose M Mato, Maria L Martinez-Chantar, Ana M Aransay

Department of Public Health

17 Citations (Scopus)

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.

Original language	English
Journal	Hepatology
Volume	57
Issue number	2
Pages (from-to)	505-514
Number of pages	10
ISSN	0270-9139
DOIs	https://doi.org/10.1002/hep.26052
Publication status	Published - Feb 2013

Keywords

Adolescent
Adult
Aged
Diabetes Mellitus, Type 2
Fatty Liver
Female
Gene Frequency
Gene Silencing
Genetic Predisposition to Disease
Glucose Transporter Type 1
Humans
Male
Middle Aged
Oleic Acid
Oxidative Stress
Polymorphism, Single Nucleotide
Transcriptome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/hep.26052

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Vazquez-Chantada, M., Gonzalez-Lahera, A., Martinez-Arranz, I., Garcia-Monzon, C., Regueiro, M. M., Garcia-Rodriguez, J. L., Schlangen, K. A., Mendibil, I., Rodriguez-Ezpeleta, N., Lozano, J. J., Banasik, K., Justesen, J. M., Jørgensen, T., Witte, D. R., Lauritzen, T., Hansen, T., Pedersen, O., Veyrie, N., Clement, K., ... Aransay, A. M. (2013). Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease. Hepatology, 57(2), 505-514. https://doi.org/10.1002/hep.26052

Vazquez-Chantada, M, Gonzalez-Lahera, A, Martinez-Arranz, I, Garcia-Monzon, C, Regueiro, MM, Garcia-Rodriguez, JL, Schlangen, KA, Mendibil, I, Rodriguez-Ezpeleta, N, Lozano, JJ, Banasik, K , Justesen, JM, Jørgensen, T, Witte, DR, Lauritzen, T, Hansen, T , Pedersen, O, Veyrie, N, Clement, K, Tordjman, J, Tran, A, Le Marchand-Brustel, Y, Buque, X, Aspichueta, P, Echevarria-Uraga, JJ, Martin-Duce, A, Caballeria, J, Gual, P, Castro, A, Mato, JM, Martinez-Chantar, ML & Aransay, AM 2013, 'Solute carrier family 2 member 1 is involved in the development of nonalcoholic fatty liver disease', Hepatology, vol. 57, no. 2, pp. 505-514. https://doi.org/10.1002/hep.26052

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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.",

keywords = "Adolescent, Adult, Aged, Diabetes Mellitus, Type 2, Fatty Liver, Female, Gene Frequency, Gene Silencing, Genetic Predisposition to Disease, Glucose Transporter Type 1, Humans, Male, Middle Aged, Oleic Acid, Oxidative Stress, Polymorphism, Single Nucleotide, Transcriptome",

author = "Mercedes Vazquez-Chantada and Aintzane Gonzalez-Lahera and Ibon Martinez-Arranz and Carmelo Garcia-Monzon and Regueiro, {Manuela M} and Garcia-Rodriguez, {Juan L} and Schlangen, {Karin A} and I{\~n}aki Mendibil and Naiara Rodriguez-Ezpeleta and Lozano, {Juan J} and Karina Banasik and Justesen, {Johanne M} and Torben J{\o}rgensen and Witte, {Daniel R} and Torsten Lauritzen and Torben Hansen and Oluf Pedersen and Nicolas Veyrie and Karine Clement and Joan Tordjman and Albert Tran and {Le Marchand-Brustel}, Yannik and Xabier Buque and Patricia Aspichueta and Echevarria-Uraga, {Jose J} and Antonio Martin-Duce and Joan Caballeria and Philippe Gual and Azucena Castro and Mato, {Jose M} and Martinez-Chantar, {Maria L} and Aransay, {Ana M}",

note = "Copyright {\textcopyright} 2012 American Association for the Study of Liver Diseases.",

year = "2013",

month = feb,

doi = "10.1002/hep.26052",

language = "English",

volume = "57",

pages = "505--514",

journal = "Hepatology",

issn = "0270-9139",

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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

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 -

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

Abstract

Keywords

UN SDGs

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