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
Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, Monica, USA.
JHEP Rep. 2020 Apr 20;2(4):100117. doi: 10.1016/j.jhepr.2020.100117. eCollection 2020 Aug.
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.
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.
准确确定非酒精性脂肪性肝病（NAFLD）的发病具有挑战性。因此，肝脏对脂肪堆积的初始反应，这可能是我们理解NAFLD演变和临床结局的基础，但在很大程度上尚不清楚。在此，我们按时间顺序绘制了小鼠脂肪肝疾病早期肝脏中的免疫和代谢变化，并将其与人类NAFLD样本进行比较。
收集NAFLD患者（NAFLD活动评分[NAS]2 - 3）的肝活检组织进行基因表达谱分析。小鼠短期接受高脂饮食以模拟初始脂肪变性，并使用共聚焦活体成像、基因表达、细胞分离、流式细胞术和骨髓移植试验相结合的方法研究肝脏免疫反应。
我们在NAS 2 - 3的患者和NAFLD初始阶段的小鼠中观察到主要的免疫变化。在小鼠中，这些变化显著增加了药物性肝损伤后的死亡率，并使小鼠易患细菌感染。此外，肝细胞中Toll样受体4的缺失减弱了饮食损伤初始阶段的耐受性形成，尤其是在库普弗细胞中。
肝脏免疫系统作为肝脏脂质含量早期微小变化的哨兵，在饮食损伤时产生双相反应。肠道来源的Toll样受体4配体对肝脏免疫细胞的启动在初始阶段的肝脏耐受性中起重要作用，但持续暴露于损伤可能导致损伤并降低控制感染的能力。
脂肪肝是一种非常常见的肝脏疾病形式，每年导致数百万例肝硬化病例。患者在病情严重之前通常没有症状。因此，扩大我们对疾病发病早期阶段的认识以实现早期诊断非常重要。在此，我们表明即使在脂肪肝疾病的早期阶段，参与炎症反应的基因也有显著改变，这表明即使肝脏脂肪含量发生微小且难以检测的变化，肝脏免疫系统也会受到干扰。这可能对脂肪肝疾病的诊断和临床管理产生影响。
