title: Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is a consequence of defects in diverse metabolic pathways that involve hepatic accumulation of triglycerides. Features of these aberrations might determine whether NAFLD progresses to nonalcoholic steatohepatitis (NASH). We investigated whether the diverse defects observed in patients with NAFLD are caused by different NAFLD subtypes with specific serum metabolomic profiles, and whether these can distinguish patients with NASH from patients with simple steatosis.
  
  
  
  We collected liver and serum from methionine adenosyltransferase 1a knockout (MAT1A-KO) mice, which have chronically low levels of hepatic S-adenosylmethionine (SAMe) and spontaneously develop steatohepatitis, as well as C57Bl/6 mice (controls); the metabolomes of all samples were determined. We also analyzed serum metabolomes of 535 patients with biopsy-proven NAFLD (353 with simple steatosis and 182 with NASH) and compared them with serum metabolomes of mice. MAT1A-KO mice were also given SAMe (30 mg/kg/day for 8 weeks); liver samples were collected and analyzed histologically for steatohepatitis.
  
  
  
  Livers of MAT1A-KO mice were characterized by high levels of triglycerides, diglycerides, fatty acids, ceramides, and oxidized fatty acids, as well as low levels of SAMe and downstream metabolites. There was a correlation between liver and serum metabolomes. We identified a serum metabolomic signature associated with MAT1A-KO mice that also was present in 49% of the patients; based on this signature, we identified 2 NAFLD subtypes. We identified specific panels of markers that could distinguish patients with NASH from patients with simple steatosis for each subtype of NAFLD. Administration of SAMe reduced features of steatohepatitis in MAT1A-KO mice.
  
  
  
  In an analysis of serum metabolomes of patients with NAFLD and MAT1A-KO mice with steatohepatitis, we identified 2 major subtypes of NAFLD and markers that differentiate steatosis from NASH in each subtype. These might be used to monitor disease progression and identify therapeutic targets for patients.
authors.affiliation: OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alonso
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Ibon
authors.initials: I
authors.lastname: Martínez-Arranz
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Navasa
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Sebastiaan M
authors.initials: SM
authors.lastname: Van Liempd
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Lavín Trueba
authors.affiliation: OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Mayo
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Concetta P
authors.initials: CP
authors.lastname: Ilisso
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Virginia G
authors.initials: VG
authors.lastname: de Juan
authors.affiliation: OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Iruarrizaga-Lejarreta
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: delaCruz-Villar
authors.affiliation: OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Mincholé
authors.affiliation: Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Aaron
authors.initials: A
authors.lastname: Robinson
authors.affiliation: Gastroenterology and Hepatology Department, Infection, Immunity and Digestive Pathology Group, IDIVAL, Instituto de Investigación Valdecilla, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Faculty of Medicine and Health Science, Hospital Universitario Príncipe de Asturias, Alcalá University, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Martín-Duce
authors.affiliation: Unidad de Enfermedades Digestivas, Hospital Virgen de Valme, Hospital Universitario Virgen Macarena y Virgen del Rocío, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, CIBERehd, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gómez
authors.affiliation: Abbott Laboratories GmbH, Hannover, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sann
authors.affiliation: Abbott, Allschwil, Switzerland.
authors.forename: Julian
authors.initials: J
authors.lastname: Platon
authors.affiliation: Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Eyk
authors.affiliation: Department of Physiology, University of the Basque Country, Biocruces Research Institute, Barakaldo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Mazen
authors.initials: M
authors.lastname: Noureddin
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Falcón-Pérez
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: María Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.affiliation: CIC bioGUNE, CIBERehd, Parque Tecnológico de Bizkaia, Derio, Spain. Electronic address: jmmato@cicbiogune.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002518:Ceramides / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D055442:Metabolome; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood* / Q000145:classification* / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002518:Ceramides; D004075:Diglycerides; D005227:Fatty Acids; D014280:Triglycerides; D012436:S-Adenosylmethionine; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase
keywords: 1-Carbon Metabolism; Lipid Metabolism; Mouse Model; Prognostic