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

Autor:	Diniz AB; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Antunes MM; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Lacerda VAS; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Nakagaki BN; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Freitas Lopes MA; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Castro-Oliveira HM; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Mattos MS; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Mafra K; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., de Miranda CDM; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., de Oliveira Costa KM; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Lopes ME; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Alvarenga DM; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Carvalho-Gontijo R; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, Monica, USA., Marchesi SC; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Lacerda DR; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., de Araújo AM; Department of Pharmacodynamics, University of Florida, College of Pharmacy, Gainesville, FL, USA., de Carvalho É; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., David BA; University of Calgary, Alberta, T2N 4N1, Canada., Santos MM; Laboratório de Morfologia, Departamento de Biologia Animal, Universidade Federal de Viçosa, Viçosa, Brazil., Lima CX; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Silva Gomes JA; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Minto Fontes Cal TC; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., de Souza BR; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Couto CA; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Faria LC; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Teixeira Vidigal PV; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Matos Ferreira AV; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Radhakrishnnan S; Research Diet, Inc., New Brunswick, USA., Ricci M; Research Diet, Inc., New Brunswick, USA., Oliveira AG; Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil., Rezende RM; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Menezes GB; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2020 Apr 20; Vol. 2 (4), pp. 100117. Date of Electronic Publication: 2020 Apr 20 (Print Publication: 2020).
DOI:	10.1016/j.jhepr.2020.100117
Abstrakt:	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. Lay Summary: 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. Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2020 The Author(s).)
Databáze:	MEDLINE
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