Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease.

dc.contributor.authorMcGlinchey, Aidan J
dc.contributor.authorGovaere, Olivier
dc.contributor.authorGeng, Dawei
dc.contributor.authorRatziu, Vlad
dc.contributor.authorAllison, Michael
dc.contributor.authorBousier, Jerome
dc.contributor.authorPetta, Salvatore
dc.contributor.authorde Oliviera, Claudia
dc.contributor.authorBugianesi, Elisabetta
dc.contributor.authorSchattenberg, Jörn M
dc.contributor.authorDaly, Ann K
dc.contributor.authorHyötyläinen, Tuulia
dc.contributor.authorAnstee, Quentin M
dc.contributor.authorOrešič, Matej
dc.contributor.orcidGovaere, Olivier [0000-0002-4426-6930]
dc.contributor.orcidAllison, Michael [0000-0003-3677-3294]
dc.contributor.orcidBugianesi, Elisabetta [0000-0002-0502-4381]
dc.contributor.orcidSchattenberg, Jörn M [0000-0002-4224-4703]
dc.descriptionFunder: European Commission
dc.description.abstractBACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). METHODS: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. RESULTS: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. CONCLUSIONS: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. CLINICAL TRIALS REGISTRATION: The study is registered at (NCT04442334). LAY SUMMARY: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.sourcenlmid: 101761237
dc.sourceessn: 2589-5559
dc.subject2-HB, 2-hydroxybutanoic acid
dc.subject3-HB, 3-hydroxybutanoic acid
dc.subjectALT, alanine aminotransferase
dc.subjectAST, aspartate aminotransferase
dc.subjectCE, cholesterol ester
dc.subjectCer, ceramide
dc.subjectFFA, free fatty acid
dc.subjectFLIP, Fatty Liver Inhibition of Progression
dc.subjectGC, gas chromatography
dc.subjectHCC, hepatocellular carcinoma
dc.subjectHSD, honest significant difference
dc.subjectLC, lipid cluster
dc.subjectLDL, low-density lipoprotein
dc.subjectLM, lipid and metabolite
dc.subjectLMC, lipid, metabolite, and clinical variable
dc.subjectLPC, lysophosphatidylcholine
dc.subjectMass spectrometry
dc.subjectNAFL, non-alcoholic fatty liver
dc.subjectNAFLD, non-alcoholic fatty liver disease
dc.subjectNAS, NASH activity score
dc.subjectNASH, non-alcoholic steatohepatitis
dc.subjectNIDDK NASH-CRN, National Institute of Digestive Diseases and Kidney NASH Clinical Research Network
dc.subjectNRR, non-rejection rate
dc.subjectNon-alcoholic steatohepatitis
dc.subjectPC(O), ether PC
dc.subjectPC, phosphatidylcholine
dc.subjectPCA, principal component analysis
dc.subjectPE, phosphatidylethanolamine
dc.subjectQTOFMS, quadrupole-time-of-flight mass spectrometry
dc.subjectROC, receiving operator characteristic
dc.subjectSAF, steatosis, activity, and fibrosis
dc.subjectSM, sphingomyelin
dc.subjectT2DM, type 2 diabetes mellitus
dc.subjectTG, triacylglycerol
dc.subjectUHPLC, ultrahigh-performance liquid chromatography
dc.titleMetabolic signatures across the full spectrum of non-alcoholic fatty liver disease.
prism.publicationNameJHEP Rep
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