1 Institute for Experimental Surgery, University Medicine Rostock, Rostock 18057, Germany.
2 QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia.
Exp Biol Med (Maywood). 2018 Jan;243(1):1-12. doi: 10.1177/1535370217738730. Epub 2017 Oct 24.
Non-alcoholic fatty liver disease is closely associated with metabolic syndrome and comprises a pathological spectrum of liver disease ranging from steatosis to steatohepatitis and can progress to fibrosis/cirrhosis and hepatocellular carcinoma. In 2013, a mouse model was described that mimics non-alcoholic fatty liver disease progression from steatohepatitis to tumors in a short time span and with high incidence. As microcirculatory disturbances play a crucial role in liver disease, the suitability of the steatosis-inflammation-tumor model for microcirculatory studies was assessed. Herein, we present a comprehensive view on morphological, microvascular, cellular, and functional aspects of non-alcoholic fatty liver disease progression in the steatosis-inflammation-tumor model using intravital microscopy, biochemical, and histological techniques. Mice develop steatohepatitis, mild fibrosis, and liver tumors at ages of 6, 12, and 20 weeks, respectively. Non-alcoholic fatty liver disease progression was accompanied by several general aspects of disease severity like increasing liver/body weight index, non-alcoholic fatty liver disease activity score, and hepatocellular apoptosis. Intravital microscopic analysis revealed significant changes in hepatic microcirculation with increasing structural alterations, elevated leukocyte adherence, and impaired nutritive perfusion. Non-alcoholic fatty liver disease was further characterized by a lower sinusoidal density with a striking rise at 20 weeks. The characteristic microcirculatory changes make the model a convenient tool for analysis of microcirculation during progression from steatosis to liver tumor. Impact statement Significant alterations of microcirculation contribute to progression of NAFLD, a chronic liver disease with increasing medical and socio-economic impact. Characterization of microcirculation in a NAFLD model reflecting all relevant stages of disease progression was still missing. Thus, we evaluated microcirculatory and cellular changes in a steatosis-inflammation-tumor model using in vivo microscopy. Analyses revealed increasing structural alterations, elevated leukocyte-endothelial interaction, and impaired nutritive perfusion. Thus, this model is suitable for further studies investigating therapeutic approaches targeting these progressive microcirculatory disturbances.
非酒精性脂肪性肝病与代谢综合征密切相关，包括从脂肪变性到脂肪性肝炎的肝脏疾病病理谱，并可进展为纤维化/肝硬化和肝细胞癌。2013 年，描述了一种小鼠模型，该模型可在短时间内以高发生率模拟非酒精性脂肪性肝炎向肿瘤的进展。由于微循环紊乱在肝病中起着至关重要的作用，因此评估了脂肪变性-炎症-肿瘤模型在微循环研究中的适用性。在这里，我们使用活体显微镜、生化和组织学技术，对脂肪变性-炎症-肿瘤模型中非酒精性脂肪性肝病进展的形态、微血管、细胞和功能方面进行了全面的观察。小鼠分别在 6、12 和 20 周时发展为脂肪性肝炎、轻度纤维化和肝肿瘤。非酒精性脂肪性肝病的进展伴随着一些疾病严重程度的一般方面，如肝/体重指数增加、非酒精性脂肪性肝病活动评分和肝细胞凋亡增加。活体显微镜分析显示，随着结构改变、白细胞黏附增加和营养灌注受损，肝微循环发生显著变化。非酒精性脂肪性肝病的特征还在于窦状密度降低，而在 20 周时则急剧升高。该模型的特征性微循环变化使其成为分析从脂肪变性到肝肿瘤进展过程中微循环的便捷工具。影响描述 微循环的显著改变有助于非酒精性脂肪性肝病的进展，非酒精性脂肪性肝病是一种慢性肝病，其医疗和社会经济影响日益增加。在反映疾病进展所有相关阶段的非酒精性脂肪性肝病模型中，对微循环进行特征描述仍然存在空白。因此，我们使用活体显微镜评估了脂肪变性-炎症-肿瘤模型中的微循环和细胞变化。分析显示结构改变增加、白细胞-内皮相互作用增加和营养灌注受损。因此，该模型适合进一步研究针对这些进行性微循环紊乱的治疗方法。
