RT Journal Article
T1 Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.
A1 Alonso, Cristina
A1 Fernández-Ramos, David
A1 Varela-Rey, Marta
A1 Martínez-Arranz, Ibon
A1 Navasa, Nicolás
A1 Van Liempd, Sebastiaan M
A1 Lavín Trueba, José L
A1 Mayo, Rebeca
A1 Ilisso, Concetta P
A1 de Juan, Virginia G
A1 Iruarrizaga-Lejarreta, Marta
A1 delaCruz-Villar, Laura
A1 Mincholé, Itziar
A1 Robinson, Aaron
A1 Crespo, Javier
A1 Martín-Duce, Antonio
A1 Romero-Gómez, Manuel
A1 Sann, Holger
A1 Platon, Julian
A1 Van Eyk, Jennifer
A1 Aspichueta, Patricia
A1 Noureddin, Mazen
A1 Falcón-Pérez, Juan M
A1 Anguita, Juan
A1 Aransay, Ana M
A1 Martínez-Chantar, María Luz
A1 Lu, Shelly C
A1 Mato, José M
K1 1-Carbon Metabolism
K1 Lipid Metabolism
K1 Mouse Model
K1 Prognostic
AB 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.
YR 2017
FD 2017-01-26
LK http://hdl.handle.net/10668/10816
UL http://hdl.handle.net/10668/10816
LA en
DS RISalud
RD Apr 13, 2025