Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis
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
DOI:
10.1053/j.gastro.2017.01.015
Publication Date:
2017-01-26T16:48:48Z
AUTHORS (28)
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (39)
CITATIONS (230)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....