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Barr J.,OWL | Caballeria J.,Hospital Clinic | Martinez-Arranz I.,OWL | Dominguez-Diez A.,University of Cantabria | And 28 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.


PubMed | ICAN Institute Cardiometabolisme et Nutrition
Type: Comparative Study | Journal: Journal of hepatology | Year: 2012

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.Biopsies of the liver, sSAT, dSAT, and VAT were collected in 45 subjects with morbid obesity (age 43.71.6 years; BMI 48.51.2kg/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.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.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.

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