Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan; Division of Gastroenterological and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan.
Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
Am J Pathol. 2021 Sep;191(9):1580-1591. doi: 10.1016/j.ajpath.2021.06.001. Epub 2021 Jun 11.
Nonalcoholic fatty liver disease often progresses to cirrhosis and causes liver cancer, but mechanisms of its progression are yet to be elucidated. Although nonalcoholic fatty liver disease is often associated with abnormal portal circulation, there have not been any experimental studies to test its pathogenic role. Here, whether decreased portal circulation affected the pathology of nonalcoholic steatohepatitis (NASH) was examined using congenital portosystemic shunt (PSS) in C57BL/6J mice. Whereas PSS significantly attenuated free radical-mediated carbon tetrachloride injury, it augmented pericellular fibrosis in the centrilobular area induced by a 0.1% methionine choline-deficient l-amino acid-defined high-fat diet (CDAHFD). PSS aggravated ductular reaction and increased the expression of connective tissue growth factor. Pimonidazole immunohistochemistry of the liver revealed that the centrilobular area of PSS-harboring mice was more hypoxic than that of control mice. Although tissue hypoxia was observed in the fibrotic area in CDAHFD-induced NASH in both control and PSS-harboring mice, it was more profound in the latter, which was associated with higher carbonic anhydrase 9 and vascular endothelial growth factor expression and neovascularization in the fibrotic area. Furthermore, partial ligation of the portal vein also augmented pericellular fibrosis and ductular reaction induced by a CDAHFD. These results demonstrate that decreased portal circulation, which induces hypoxia due to disrupted intralobular perfusion, is an important aggravating factor of liver fibrosis in NASH.
非酒精性脂肪性肝病常进展为肝硬化并导致肝癌，但其进展的机制尚未阐明。尽管非酒精性脂肪性肝病常伴有门脉循环异常，但尚未有任何实验研究来检验其致病作用。在这里，通过 C57BL/6J 小鼠的先天性门体分流（PSS）来研究门脉循环减少是否会影响非酒精性脂肪性肝炎（NASH）的病理学。虽然 PSS 显著减轻了自由基介导的四氯化碳损伤，但它加剧了由 0.1%蛋氨酸胆碱缺乏 l-氨基酸定义的高脂肪饮食（CDAHFD）引起的中央区细胞周纤维化。PSS 加重了胆管反应并增加了结缔组织生长因子的表达。肝脏的匹莫硝唑免疫组化显示，PSS 携带小鼠的中央区比对照小鼠更缺氧。尽管在 CDAHFD 诱导的 NASH 中，对照和 PSS 携带小鼠的纤维化区域都观察到组织缺氧，但后者更为严重，这与该区域更高的碳酸酐酶 9 和血管内皮生长因子表达以及新生血管形成有关。此外，门静脉部分结扎也加剧了 CDAHFD 诱导的细胞周纤维化和胆管反应。这些结果表明，由于小叶内灌注破坏导致的门脉循环减少是 NASH 中肝纤维化的一个重要加重因素。
