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Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution

Nature Metabolism volume 1, pages 604–614 (2019)Cite this article

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Abstract

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. The presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of patients with NASH before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed non-alcoholic fatty liver disease (NAFLD) reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity on LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intrahepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.

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Fig. 1: Identification of hepatic transcriptomic signature of NASH.
Fig. 2: Correlations between blood immune cell populations, disease activity in NASH and genes in module ‘blue’.
Fig. 3: A diet-induced NASH model alters cDC and CD8 T cells and inflammation in the liver.
Fig. 4: NASH and T2D alter activity of cytotoxic CD8 T cells.
Fig. 5: Hepatic CD8 T lymphocytes correlate with lobular inflammation, ballooning and transcriptomic signature of NASH.

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Data availability

Microarray data used in this study were from the Gene Expression Omnibus repository under accession number GSE106737 and GSE83452. Requests for other data should be made to the corresponding author.

Change history

  • 24 June 2019

    In the version of this article initially published, ANR grant ANR-16-RHUS-0006 to author Joel T. Haas was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by grants from the ANR and the European Union: nos. EGID ANR-10-LABX-46 and Fondation Leducq LEAN 16CVD01 (to B.S., D.D. and P.L.), no. ANR-18 NASHILCCD8 (to B.S. and D.D.) no. FP6 HEPADIP LSHM-CT-2005-018734 (to B.S., A.V., L.V.G. and S. Francque) and no. FP7-HEALTH RESOLVE 305707 (to B.S., A.V., L.V.G. and S. Francque). S. Francque is a recipient of the Flanders Fund for Scientific Research (FWO klinisch mandaat no. 1802154N). B.S. is a recipient of an Advanced European Research Council grant (no. 694717). J.T.H. was supported by an EMBO Long Term Fellowship (no. ALTF277-2014) and by ANR grant ANR-16-RHUS-0006.

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Author notes

  1. These authors contributed equally: Joel T. Haas, Luisa Vonghia, Denis A. Mogilenko.

  2. These authors jointly supervised this work: Bart Staels, Sven Francque, David Dombrowicz.

Authors and Affiliations

  1. University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France

    Joel T. Haas, Denis A. Mogilenko, Olivier Molendi-Coste, Sébastien Fleury, Audrey Deprince, Artemii Nikitin, Eloïse Woitrain, Lucie Ducrocq-Geoffroy, Samuel Pic, Bruno Derudas, Hélène Dehondt, Céline Gheeraert, Philippe Lefebvre, Bart Staels & David Dombrowicz

  2. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium

    Luisa Vonghia & Sven Francque

  3. Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Luisa Vonghia, An Verrijken, Luc Van Gaal & Sven Francque

  4. Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

    An Verrijken & Luc Van Gaal

  5. Department of Pathology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

    Ann Driessen

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Contributions

L.V. and S. Francque collected human biopsies, histological and biochemical data. L.V., S. Francque, L.V.G. and A.V. supervised the human biopsies collection and analysis. A. Driessen performed the histology of the liver biopsies. J.T.H. and D.A.M. performed mouse experiments, flow cytometry, immunological and transcriptomic analysis, and WGCNA. S. Fleury performed immunohistochemistry. B.D., H.D., C.G. and P.L. performed microarray analysis. O.M.-C., A. Deprince, A.N., E.W., L.D.G. and S.P. performed mouse experiments and flow cytometry. D.A.M., L.V., J.T.H., S. Francque, B.S. and D.D. conceived the study, interpreted data and wrote the manuscript.

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Correspondence to Luisa Vonghia or David Dombrowicz.

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Competing interests

B.S. and S. Francque are consultants for Genfit S.A. S. Francque and LV are consultants for Inventiva. All other authors have nothing to declare.

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Haas, J.T., Vonghia, L., Mogilenko, D.A. et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab 1, 604–614 (2019). https://doi.org/10.1038/s42255-019-0076-1

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