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Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.

Key points

  • Nonalcoholic fatty liver disease (NAFLD) affects 25% of the adult world population; in about 20% of patients, it can progress to nonalcoholic steatohepatitis (NASH), which can lead to cirrhosis.

  • There is an urgent need for development of clinically relevant biomarkers and non-invasive diagnostic tests for NAFLD.

  • Metabolomics and lipidomics approaches have provided insightful evidence of altered metabolic pathways in NAFLD and NASH.

  • There is an association between circulating amino acids and steatohepatitis, and impairment in amino acid metabolism in NAFLD is strongly correlated with insulin resistance, particularly in the muscle.

  • An increase in oxidative stress results in a reduction in hepatic glutathione levels and is associated with liver damage and the progression of NAFLD to NASH.

  • NASH is strongly associated with alterations in circulating fatty acids and intact lipids, which is partially due to alterations in de novo liver lipogenesis, lipolysis rate and VLDL metabolism.

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Fig. 1: Overview of analytical approaches and workflows as commonly applied in metabolomic analysis, including lipidomics.
Fig. 2: Overview of the key metabolic pathways in fasting and postprandial states involved in the pathogenesis of NAFLD.
Fig. 3: Overview of the key bile acid pathways involved in NAFLD.
Fig. 4: Fluxomics in the insulin-resistant state in NAFLD.

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Acknowledgements

All authors of this manuscript are members of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) Consortium. The authors are supported by the EU’s Horizon 2020 Programme under the EPoS project (grant no. 634413) and the Innovative Medicines Initiative 2 Joint Undertaking under the LITMUS project (grant no. 777377) and Swiss National Science Foundation (SNSF) (grant no. 190686). This Joint Undertaking receives support from the EU’s Horizon 2020 programme and EFPIA.

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M.M. researched data for the article, made a substantial contribution to discussion of content, wrote the first draft, and reviewed/edited the manuscript before submission. A.G. and T.H. made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. E.A. researched data for the article and wrote the article. C.A. and M.G. researched data for the article, and reviewed/edited the manuscript before submission. J.B., Q.M.A., O.M., P.O. and J.M.M. reviewed/edited the manuscript before submission. J.-F.D. made a substantial contribution to discussion of content, and reviewed/edited the manuscript before submission. M.O. researched data for the article, made a substantial contribution to discussion of content, contributed to writing and reviewed/edited the manuscript before submission.

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Correspondence to Mojgan Masoodi or Matej Orešič.

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J.B. was an employee and shareholder of Pfizer. E.A., C.A. and P.O. are employees of OWL Metabolomics. A.G. is a consultant for Eli Lilly, Inventiva, Genentech, Menarini, Gilead, Novo Nordisk, AstraZeneca and Boehringer outside the submitted work. J.-F.D. is on advisory committees for Abbvie, Bayer, BMS, Falk, Genfit, Genkyotex, Gilead Science, HepaRegenix, Intercept, Lilly, Merck and Novartis; speaking and teaching at Bayer, BMS, Intercept, Genfit, Gilead Science and Novartis. Q.M.A. has active research collaborations (including research collaborations supported through the EU IMI2 LITMUS Consortium*) with Abbvie, Antaros Medical*, Allergan/Tobira*, AstraZeneca*, BMS*, Boehringer Ingelheim International GMBH*, Echosens*, Ellegaard Gottingen Minipigs AS*, Eli Lilly & Company Ltd.*, Exalenz Bioscience Ltd.*, Genfit SA*, Glympse Bio, GlaxoSmithKline, HistoIndex*, Intercept Pharma Europe Ltd.*, iXscient Ltd.*, Nordic Bioscience*, Novartis Pharma AG*, Novo Nordisk A/S*, One Way Liver SL*, Perspectum Diagnostics*, Pfizer Ltd.*, Resoundant*, Sanofi-Aventis Deutschland GMBH*, SomaLogic Inc.* and Takeda Pharmaceuticals International SA*, acts as a consultant for 89Bio, Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Celgene, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Servier, Terns, Viking Therapeutics and Speaker for Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes and MedScape, and has received royalties from Elsevier Ltd (Davidson’s Principles & Practice of Medicine textbook). All other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks C. Pirola, F. Bril and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Masoodi, M., Gastaldelli, A., Hyötyläinen, T. et al. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat Rev Gastroenterol Hepatol 18, 835–856 (2021). https://doi.org/10.1038/s41575-021-00502-9

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