Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan; Department of Food Science and Nutrition, Nara Women's University, Nara, Japan.
Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Am J Pathol. 2022 Jan;192(1):31-42. doi: 10.1016/j.ajpath.2021.10.002. Epub 2021 Oct 25.
While the interaction of cells such as macrophages and hepatic stellate cells is known to be involved in the generation of fibrosis in nonalcoholic steatohepatitis (NASH), the mechanism remains unclear. This study employed a high-fat/cholesterol/cholate (HFCC) diet to generate a model of NASH-related fibrosis to investigate the pathogenesis of fibrosis. Two mouse strains: C57BL/6J, the one susceptible to obesity, and A/J, the one relatively resistant to obesity, developed hepatic histologic features of NASH, including fat deposition, intralobular inflammation, hepatocyte ballooning, and fibrosis, after 9 weeks of HFCC diet. The severity of hepatic inflammation and fibrosis was greater in A/J mice than in the C57BL/6J mice. A/J mice fed HFCC diet exhibited characteristic CD204-positive lipid-laden macrophage aggregation in hepatic parenchyma. Polarized light was used to visualize the Maltese cross, cholesterol crystals within the aggregated macrophages. Fibrosis developed in a ring shape from the periphery of the aggregated macrophages such that the starting point of fibrosis could be visualized histologically. Matrix-assisted laser desorption/ionization mass spectrometry imaging analysis detected a molecule at m/z 772.462, which corresponds to the protonated ion of phosphatidylcholine [P-18:1 (11Z)/18:0] and phosphatidylethanolamine [18:0/20:2 (11Z, 14Z)], in aggregated macrophages adjacent to the fibrotic lesions. In conclusion, the HFCC diet-fed A/J model provides an ideal tool to study fibrogenesis and enables novel insights into the pathophysiology of NASH-related fibrosis.
虽然已知巨噬细胞和肝星状细胞等细胞的相互作用参与了非酒精性脂肪性肝炎 (NASH) 纤维化的产生，但机制仍不清楚。本研究采用高脂肪/胆固醇/胆盐 (HFCC) 饮食建立 NASH 相关纤维化模型，以研究纤维化的发病机制。两种小鼠品系：易肥胖的 C57BL/6J 和相对不易肥胖的 A/J，在接受 HFCC 饮食 9 周后，发展出 NASH 的肝组织学特征，包括脂肪沉积、小叶内炎症、肝细胞气球样变和纤维化。A/J 小鼠的肝炎症和纤维化严重程度大于 C57BL/6J 小鼠。A/J 小鼠喂食 HFCC 饮食后，肝实质中可见特征性的 CD204 阳性富含脂质的巨噬细胞聚集。偏光显微镜用于可视化聚集巨噬细胞内的马耳他十字形胆固醇晶体。纤维化呈环状从聚集巨噬细胞的外围发展，使得纤维化的起点可以在组织学上可视化。基质辅助激光解吸/电离质谱成像分析检测到质荷比为 772.462 的分子，对应于磷脂酰胆碱 [P-18:1 (11Z)/18:0] 和磷脂酰乙醇胺 [18:0/20:2 (11Z, 14Z)] 的质子化离子，在纤维化病变附近的聚集巨噬细胞中。总之，HFCC 饮食喂养的 A/J 模型为研究纤维化发生提供了理想的工具，并为 NASH 相关纤维化的病理生理学提供了新的见解。
