title: Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.
abstract: 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 individual's 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.
authors.affiliation: OWL, Derio, Bizkaia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Barr
authors.forename: J
authors.initials: J
authors.lastname: Caballería
authors.forename: I
authors.initials: I
authors.lastname: Martínez-Arranz
authors.forename: A
authors.initials: A
authors.lastname: Domínguez-Díez
authors.forename: C
authors.initials: C
authors.lastname: Alonso
authors.forename: J
authors.initials: J
authors.lastname: Muntané
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Cormenzana
authors.forename: C
authors.initials: C
authors.lastname: García-Monzón
authors.forename: R
authors.initials: R
authors.lastname: Mayo
authors.forename: A
authors.initials: A
authors.lastname: Martín-Duce
authors.forename: M
authors.initials: M
authors.lastname: Romero-Gómez
authors.forename: O
authors.initials: O
authors.lastname: Lo Iacono
authors.forename: J
authors.initials: J
authors.lastname: Tordjman
authors.forename: R J
authors.initials: RJ
authors.lastname: Andrade
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Carreras
authors.forename: Y
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: A
authors.initials: A
authors.lastname: Tran
authors.forename: C
authors.initials: C
authors.lastname: Fernández-Escalante
authors.forename: E
authors.initials: E
authors.lastname: Arévalo
authors.forename: M
authors.initials: M
authors.lastname: García-Unzueta
authors.forename: K
authors.initials: K
authors.lastname: Clement
authors.forename: J
authors.initials: J
authors.lastname: Crespo
authors.forename: P
authors.initials: P
authors.lastname: Gual
authors.forename: M
authors.initials: M
authors.lastname: Gómez-Fleitas
authors.forename: M L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: A
authors.initials: A
authors.lastname: Castro
authors.forename: S C
authors.initials: SC
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Vázquez-Chantada
authors.forename: J M
authors.initials: JM
authors.lastname: Mato
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015992:Body Mass Index; D018450:Disease Progression; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers