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  • Perspective
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A researcher’s guide to preclinical mouse NASH models

Abstract

Non-alcoholic fatty liver disease (NAFLD) and its inflammatory form, non-alcoholic steatohepatitis (NASH), have quickly risen to become the most prevalent chronic liver disease in the Western world and are risk factors for the development of hepatocellular carcinoma (HCC). HCC is not only one of the most common cancers but is also highly lethal. Nevertheless, there are currently no clinically approved drugs for NAFLD, and NASH-induced HCC poses a unique metabolic microenvironment that may influence responsiveness to certain treatments. Therefore, there is an urgent need to better understand the pathogenesis of this rampant disease to devise new therapies. In this line, preclinical mouse models are crucial tools to investigate mechanisms as well as novel treatment modalities during the pathogenesis of NASH and subsequent HCC in preparation for human clinical trials. Although, there are numerous genetically induced, diet-induced and toxin-induced models of NASH, not all of these models faithfully phenocopy and mirror the human pathology very well. In this Perspective, we shed some light onto the most widely used mouse models of NASH and highlight some of the key advantages and disadvantages of the various models with an emphasis on ‘Western diets’, which are increasingly recognized as some of the best models in recapitulating the human NASH pathology and comorbidities.

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Fig. 1: Histopathological features of mouse NASH models and relevance to human pathology.
Fig. 2: A flowchart depicting which model of NASH and NASH–HCC is most suitable for the question of interest.
Fig. 3: Proposed criterion for reporting the evaluation of diet-induced mouse models of NASH.

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Acknowledgements

M. Heikenwalder was supported by a European Research Council (ERC) Consolidator grant (HepatoMetaboPath), the ERC POC (Faith), the Helmholtz Future topic Inflammation and Immunology, Zukunftssthema ‘Immunology and Inflammation’ (ZT-0027), SFB/TR 209 project ID 314905040, SFB 1479 (Project ID: 441891347), Project ID 272983813-SFBTR 179, the Rainer Hoenig Stiftung, Research Foundation Flanders (FWO)under grant 30826052 (EOS Convention MODEL-IDI) and a seed funding from HI-TRON. Funded by the German Research Foundation (DFG) as part of the Excellence Strategy of the federal and state governments — EXC 2180 — 390900677.

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Correspondence to Suchira Gallage or Mathias Heikenwalder.

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Q.M.A. is coordinator of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) consortium funded by the Innovative Medicines Initiative (IMI2) Program of the European Union under grant agreement 777377. This multi-stakeholder consortium includes industry partners and received funding from EFPIA. Q.M.A. received funding from AstraZeneca, Boehringer Ingelheim, Intercept and royalties from Elsevier. Q.M.A. received consulting fees on behalf of Newcastle University from Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGMBio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi and Terns. Q.M.A. received fees for lectures from Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape and Springer Healthcare. The other authors declare no competing interests.

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Gallage, S., Avila, J.E.B., Ramadori, P. et al. A researcher’s guide to preclinical mouse NASH models. Nat Metab 4, 1632–1649 (2022). https://doi.org/10.1038/s42255-022-00700-y

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