1. Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution
- Author
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Audrey Deprince, David Dombrowicz, Artemii Nikitin, Bart Staels, Ann Driessen, Sébastien Fleury, An Verrijken, Denis A. Mogilenko, Hélène Dehondt, Samuel Pic, Luisa Vonghia, Bruno Derudas, Sven Francque, Joel T. Haas, Philippe Lefebvre, Luc Van Gaal, Olivier Molendi-Coste, Céline Gheeraert, Lucie Ducrocq-Geoffroy, Eloise Woitrain, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Gastroenterology and Hepatology [Antwerp, Belgium], Antwerp University Hospital [Edegem] (UZA), Department of Endocrinology, Diabetology and Metabolism [Antwerp, Belgium], Department of Pathology [Antwerp, Belgium], ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Derudas, Marie-Hélène, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID
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[SDV.IMM] Life Sciences [q-bio]/Immunology ,Transcription, Genetic ,Endocrinology, Diabetes and Metabolism ,Antigen presentation ,Inflammation ,Biology ,Diet, High-Fat ,digestive system ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Non-alcoholic Fatty Liver Disease ,Physiology (medical) ,Internal Medicine ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Gene Regulatory Networks ,030304 developmental biology ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,0303 health sciences ,Microarray analysis techniques ,Fatty liver ,nutritional and metabolic diseases ,Cell Biology ,Gene signature ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,digestive system diseases ,3. Good health ,Mice, Inbred C57BL ,Liver ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,030211 gastroenterology & hepatology ,Human medicine ,Steatohepatitis ,medicine.symptom - Abstract
Luisa Vonghia and David Dombrowicz equally contributed to the work.; International audience; 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.
- Published
- 2019
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