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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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.
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.
Peer review information: Primary Handling Editors: Elena Bellafante, Christoph Schmitt.
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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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