Details

Autor(en) / Beteiligte

• Diniz, Ariane Barros
• Antunes, Maísa Mota
• Lacerda, Viviane Aparecida de Souza
• Nakagaki, Brenda Naemi
• Freitas Lopes, Maria Alice
• Castro-Oliveira, Hortência Maciel de
• Mattos, Matheus Silvério
• Mafra, Kassiana
• de Miranda, Camila Dutra Moreira
• de Oliveira Costa, Karen Marques
• Lopes, Mateus Eustáquio
• Alvarenga, Débora Moreira
• Carvalho-Gontijo, Raquel
• Marchesi, Sarah Cozzer
• Lacerda, Debora Romualdo
• de Araújo, Alan Moreira
• de Carvalho, Érika
• David, Bruna Araújo
• Santos, Mônica Morais
• Lima, Cristiano Xavier
• Silva Gomes, Juliana Assis
• Minto Fontes Cal, Tereza Cristina
• de Souza, Bruna Roque
• Couto, Cláudia Alves
• Faria, Luciana Costa
• Teixeira Vidigal, Paula Vieira
• Matos Ferreira, Adaliene Versiane
• Radhakrishnnan, Sridhar
• Ricci, Matthew
• Oliveira, André Gustavo
• Rezende, Rafael Machado
• Menezes, Gustavo Batista

Titel

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

Ist Teil von

• JHEP reports, 2020-08, Vol.2 (4), p.100117-100117, Article 100117

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. 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. 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. 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. Fatty liver is a very common form of hepatic disease, leading to millions of cases of cirrhosis every year. Patients are often asymptomatic until becoming very sick. Therefore, it is important that we expand our knowledge of the early stages of disease pathogenesis, to enable early diagnosis. Herein, we show that even in the early stages of fatty liver disease, there are significant alterations in genes involved in the inflammatory response, suggesting that the hepatic immune system is disturbed even following minor and undetectable changes in liver fat content. This could have implications for the diagnosis and clinical management of fatty liver disease. [Display omitted] •Hepatic immune response is already altered in liver biopsies from patients with mild NAFLD.•We designed a novel mouse model to mimic mild NAFLD, enabling the chronological mapping of liver changes.•This revealed an increased mortality rate upon secondary liver damage and a window of increased susceptibility to infection.•NAFLD diagnosis may be significantly improved by a more profound investigation of changes in hepatic immunology.•These data could guide customized nutritional and therapeutic interventions at different stages of NAFLD.