Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

• Autor(a) principal: Ariane Barros Diniz
• Data de Publicação: 2020
• Outros Autores: Maísa Mota Antunes, Viviane Aparecida de Souza Lacerda, Brenda Naemi Nakagak, Maria Alice Freitas Lopes, Hortência Maciel de Castro-Oliveira, Matheus Silvério Mattos, Kassiana Mafra Bicalho, Camila Dutra Moreira de Miranda, Karen Marques de Oliveira Costa, Mateus Eustáquio de Moura Lopes, Débora Moreira Alvarenga, Raquel Carvalho-Gontijo, Sarah Cozzer Marchesi, Debora Romualdo Lacerda, Alan Moreira de Araújo, Érika de Carvalho, Bruna Araújo David, Mônica Morais Santos, Cristiano Xavier Lima, Juliana Assis Silva Gomes, Tereza Cristina Minto Fontes Cal, Bruna Roque de Souza, Cláudia Alves Couto, Luciana Costa Faria, Paula Vieira Teixeira Vidigal, Adaliene Versiane Matos Ferreira, Sridhar Radhakrishnnan, Matthew Ricci, André Gustavo Oliveira, Rafael Machado Rezende, Gustavo Batista Menezes
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFMG
• Texto Completo: https://doi.org/10.1016/j.jhepr.2020.100117; http://hdl.handle.net/1843/53958; https://orcid.org/0000-0002-3137-991X; https://orcid.org/0000-0003-4600-7593; https://orcid.org/0000-0002-4926-0618; https://orcid.org/0000-0002-9163-6279; https://orcid.org/0000-0002-0184-6433; https://orcid.org/0000-0003-4779-8972; https://orcid.org/0000-0001-8730-7336; https://orcid.org/0000-0001-7909-6970; https://orcid.org/0000-0001-5157-159X; https://orcid.org/0000-0001-7724-890X; https://orcid.org/0000-0003-2256-8652; https://orcid.org/0000-0001-8307-0810; https://orcid.org/0000-0003-3998-8012
• topic: NAFLD; Liver; Steatosis; Immune system; Diet; Metabolism; In vivo imaging; Immunity; Hepatopatia gordurosa não alcoólica; Fígado; Sistema Imunitário; Dieta; Metabolismo; Imunidade

Background & Aims: The precise determination of non-alcoholic fatty liver disease (NAFLD) onset is challenging. Thus, the initial hepatic responses to fat accumulation, which may be fundamental to our understanding of NAFLD evolution and clinical outcomes, are largely unknown. Herein, we chronologically mapped the immunologic and metabolic changes in the liver during the early stages of fatty liver disease in mice and compared this with human NAFLD samples. Methods: Liver biopsies from patients with NAFLD (NAFLD activity score [NAS] 2–3) were collected for gene expression profiling. Mice received a high-fat diet for short periods to mimic initial steatosis and the hepatic immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. Results: We observed major immunologic changes in patients with NAS 2–3 and in mice in the initial stages of NAFLD. In mice, these changes significantly increased mortality rates upon drug-induced liver injury, as well as predisposing mice to bacterial infections. Moreover, deletion of Toll-like receptor 4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial stages of dietary insult. Conclusion: The hepatic immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon dietary insult. Priming of liver immune cells by gut-derived Toll-like receptor 4 ligands plays an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections.