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

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)

[1]  A. Baranova,et al.  Systematic review: the epidemiology and natural history of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis in adults , 2011, Alimentary pharmacology & therapeutics.

[2]  J. Svaren,et al.  Early Growth Response 1 (Egr1) Regulates Cholesterol Biosynthetic Gene Expression* , 2011, The Journal of Biological Chemistry.

[3]  Hongyu Zhao,et al.  A Genome-Wide Association Study on Obesity and Obesity-Related Traits , 2011, PloS one.

[4]  F. Bellanti,et al.  Mitochondrial dysfunction in nonalcoholic steatohepatitis , 2011, Expert review of gastroenterology & hepatology.

[5]  Udo Hoffmann,et al.  Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits , 2011, PLoS genetics.

[6]  R. Swerdlow,et al.  Ncb5or Deficiency Increases Fatty Acid Catabolism and Oxidative Stress* , 2011, The Journal of Biological Chemistry.

[7]  E. Brunt,et al.  Histopathology of nonalcoholic fatty liver disease. , 2010, World journal of gastroenterology.

[8]  Shelly C. Lu,et al.  Activation of LKB1‐Akt pathway independent of phosphoinositide 3‐kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis , 2010, Hepatology.

[9]  Shelly C. Lu,et al.  Liquid chromatography-mass spectrometry-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of nonalcoholic fatty liver disease. , 2010, Journal of proteome research.

[10]  Shelly C. Lu,et al.  Non‐alcoholic fatty liver disease proteomics , 2010, Proteomics. Clinical applications.

[11]  A. Baranova,et al.  Gene expression profile associated with superimposed non‐alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[12]  D. Spitz,et al.  Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells , 2009, Cancer biology & therapy.

[13]  G. Tarantino,et al.  Relationships of PAI-1 levels to central obesity and liver steatosis in a sample of adult male population in southern Italy , 2009, Internal and emergency medicine.

[14]  D. Pearce,et al.  Rictor/TORC2 Regulates Caenorhabditis elegans Fat Storage, Body Size, and Development through sgk-1 , 2009, PLoS biology.

[15]  M. Makishima,et al.  Liver X receptors (LXRα and LXRβ) are potent regulators for hepatic Dec1 expression , 2009, Genes to cells : devoted to molecular & cellular mechanisms.

[16]  Alexander Pertsemlidis,et al.  Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease , 2008, Nature Genetics.

[17]  N. Anderson,et al.  Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis , 2008, Pharmacological Reviews.

[18]  Shelly C. Lu,et al.  Methionine metabolism and liver disease. , 2008, Annual review of nutrition.

[19]  Pan Du,et al.  lumi: a pipeline for processing Illumina microarray , 2008, Bioinform..

[20]  L. Rubbia‐Brandt,et al.  Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C , 2007, Liver international : official journal of the International Association for the Study of the Liver.

[21]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[22]  J. Dopazo,et al.  From genes to functional classes in the study of biological systems , 2007, BMC Bioinformatics.

[23]  José L Sevilla,et al.  Identification of a gene-pathway associated with non-alcoholic steatohepatitis. , 2007, Journal of hepatology.

[24]  D. Golde,et al.  Vitamin C enters mitochondria via facilitative glucose transporter 1 (Gluti) and confers mitochondrial protection against oxidative injury , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[26]  M. Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[27]  M. Charlton.  Nonalcoholic fatty liver disease: a review of current understanding and future impact. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[28]  D. Allison,et al.  Nonreplication in genetic association studies of obesity and diabetes research. , 2003, The Journal of nutrition.

[29]  Charlotte Glümer,et al.  A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1) , 2003, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[30]  M. Manns,et al.  Effect of treatment with peginterferon or interferon alfa‐2b and ribavirin on steatosis in patients infected with hepatitis C , 2003, Hepatology.

[31]  E. Kabagambe,et al.  Adipose tissue biomarkers of fatty acid intake. , 2002, The American journal of clinical nutrition.

[32]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[33]  B. Decallonne,et al.  An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. , 2001, Methods.

[34]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[35]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[36]  E. Brunt.  Nonalcoholic steatohepatitis (NASH): further expansion of this clinical entity? , 1999, Liver.

[37]  P. J. Randle,et al.  Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. , 1998, Diabetes/metabolism reviews.

[38]  D. Rhoads.  Liver glut‐1 expression: An enigma deepens , 1994, Hepatology.

[39]  B. Bilir,et al.  Novel control of the position-dependent expression of genes in hepatocytes. The GLUT-1 transporter. , 1993, The Journal of biological chemistry.

[40]  A. Pfeifer,et al.  Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Fanestil,et al.  Interference by lipids in the determination of protein using bicinchoninic acid. , 1986, Analytical biochemistry.

[42]  J. Finkelstein,et al.  Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. , 1984, The Journal of biological chemistry.

[43]  B Chance,et al.  Hydroperoxide metabolism in mammalian organs. , 1979, Physiological reviews.

[44]  T Lauritzen,et al.  The ADDITION study: proposed trial of the cost-effectiveness of an intensive multifactorial intervention on morbidity and mortality among people with Type 2 diabetes detected by screening , 2000, International Journal of Obesity.

[45]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.