Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis

• DOI: 10.1053/j.gastro.2017.01.015
• Publication Date: 2017-01-26T16:48:48Z
• Authors: Cristina Alonso; David Fernández-R...; Marta Varela-Rey; Ibon Martínez-Arranz; Nicolás Navasa; Sebastiaan M. Van...; José L. Lavín Trueba; Rebeca Mayo; Concetta P. Ilisso; Virginia G. de Juan; Marta Iruarrizaga...; Laura delaCruz-Vi...; Itziar Mincholé; Aaron Robinson; Javier Crespo; Antonio Martín-Duce; Manuel Romero-Gómez; Holger Sann; Julian Platon; Jennifer Van Eyk; Patricia Aspichueta; Mazen Noureddin; Juan M. Falcón-Pérez; Juan Anguita; Ana M. Aransay; María Luz Martíne...; Shelly C. Lu; José M. Mato
• Keywords: Adult; Male; 0301 basic medicine; S-Adenosylmethionine; Knockout; Clinical Sciences; Chronic Liver Disease and Cirrhosis; 610; Clinical sciences; Inbred C57BL; Prognostic; Ceramides; Oral and gastrointestinal; Hepatitis; Paediatrics and Reproductive Medicine; Diglycerides; Mice; 03 medical and health sciences; Non-alcoholic Fatty Liver Disease; 616; Animals; Humans; Triglycerides; Mice, Knockout; Mouse Model; Biomedical and Clinical Sciences; Gastroenterology & Hepatology; Liver Disease; Fatty Acids; Neurosciences; Methionine Adenosyltransferase; Middle Aged; Lipid Metabolism; 4.1 Discovery and preclinical testing of markers and technologies; 1-Carbon Metabolism; 3. Good health; Nutrition and dietetics; Mice, Inbred C57BL; Metabolome; Female; Digestive Diseases; Biomarkers

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.