Barr J.,OWL |
Caballeria J.,Institute dInvestigacions Biomediques August Pi Sunyer IDIBAPS |
Martinez-Arranz I.,OWL |
Dominguez-Diez A.,University of Cantabria |
And 27 more authors.
Journal of Proteome Research | Year: 2012
Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n = 90) or diagnosed with NAFLD (steatosis, n = 246; NASH, n = 131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individuals level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. © 2012 American Chemical Society.
Vazquez-Chantada M.,CIBER ISCIII |
Gonzalez-Lahera A.,CIBER ISCIII |
Martinez-Arranz I.,OWL Genomics |
Garcia-Monzon C.,Hospital Universitario Santa Cristina |
And 44 more authors.
Hepatology | Year: 2013
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. © 2012 American Association for the Study of Liver Diseases.
Lafarge J.-C.,French Institute of Health and Medical Research |
Lafarge J.-C.,University Pierre and Marie Curie |
Lafarge J.-C.,University of Paris Descartes |
Lafarge J.-C.,ICAN Institute Cardiometabolisme et Nutrition |
And 8 more authors.
Clinical Reviews in Bone and Mineral Metabolism | Year: 2011
Members of the cysteine protease cathepsin family play an important part in human pathophysiology. Among those, Cathepsin K has a major role in enzymatic bone degradation. Cathepsin K was recently found to be expressed in adipose tissue and increased in obesity. This led to the hypothesis that Cathepsin K and potentially other forms of cathepsin might contribute to obesity and obesity-linked complications. In this context, we identified Cathepsin S gene as one of the most deregulated gene in the adipose tissue of obese subjects, showing a strong correlation with body mass index, while Cathepsin L was also found in high abundance in the adipose tissue of diet-induced and genetically obese mice. Cathepsin K or Cathepsin L deletion in genetically modified mice reduces adiposity and ameliorates glucose homeostasis. The pharmacological inhibition of these cathepsins attenuates body weight gain both in diet-induced and in genetically obese mice and impairs adipose differentiation in cell culture experiments. These data in mice and humans enlighten the unexpected implication of cathepsin family members to promote fat accretion and contribute to the deterioration of glycemic parameters in obesity. Thus, inhibition of specific cathepsins might prove an efficient adjunct to diet and exercise in human obesity, notwithstanding it remains to decipher the cellular and molecular mechanisms implicated. © 2011 Springer Science+Business Media, LLC.
Tordjman J.,ICAN Institute Cardiometabolisme et Nutrition |
Tordjman J.,French Institute of Health and Medical Research |
Tordjman J.,University Pierre and Marie Curie |
Divoux A.,French Institute of Health and Medical Research |
And 26 more authors.
Journal of Hepatology | Year: 2012
Background & Aims: In addition to total body fat, the regional distribution and inflammatory status of enlarged adipose tissue are strongly associated with metabolic co-morbidities of obesity. We recently showed that the severity of histological liver lesions related to obesity increases with the amount of macrophage accumulation in visceral adipose tissue (VAT), while no association was found with the subcutaneous adipose tissue (SAT). In the abdominal region, SAT is anatomically divided into two layers, i.e. superficial (sSAT) and deep (dSAT). The aim of the present study was to test the hypothesis that these distinct compartments differentially contribute to hepatic alterations in obesity. Methods: Biopsies of the liver, sSAT, dSAT, and VAT were collected in 45 subjects with morbid obesity (age 43.7 ± 1.6 years; BMI 48.5 ± 1.2 kg/m 2) during bariatric surgery. Large scale gene expression analysis was performed to identify the pathways that discriminate sSAT from dSAT. Adipose tissue macrophages were quantified by immunohistochemistry using HAM56 antibody in subjects scored for liver histopathology. Results: An inflammatory gene pattern discriminates between sSAT and dSAT. dSAT displayed an intermediate level of macrophage accumulation between sSAT and VAT. The abundance of macrophages in dSAT, but not in sSAT, was significantly increased in patients with non-alcoholic steatohepatitis (NASH) and/or fibroinflammatory hepatic lesions. Conclusions: These data show distinct gene signature and macrophage abundance in the two compartments of SAT, with dSAT more closely related to VAT than to sSAT in terms of inflammation and relation with the severity of liver diseases in morbid obesity. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.