Faculty of Applied Bioscience, Department of Nutritional Science and Food Safety, Tokyo University of Agriculture, Setagaya, Tokyo, Japan.
Department of Nutritional Science and Food Safety, Graduate School of Applied Bioscience, Tokyo University of Agriculture, Setagaya, Tokyo, Japan.
PLoS One. 2023 Aug 3;18(8):e0287657. doi: 10.1371/journal.pone.0287657. eCollection 2023.
Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and even hepatocellular carcinoma (HCC). The incidence of NASH-associated HCC is increasing, posing a serious public health threat. Unfortunately, the underlying pathological mechanisms, including the possible differences between neoplastic and non-neoplastic lesions, remain largely unknown. Previously, we reported a dietary mouse NASH model with a choline-deficient, methionine-lowered, L-amino-acid-defined, high-fat diet containing shortening without trans fatty acids (CDAA-HF-T[-]), which rapidly induces fibrosis and proliferative lesions in the liver. This study aimed to develop a mouse CDAA-HF-T(-) model capable of assessing NASH-associated hepatocarcinogenesis and identifying key signaling factors involved in its underlying mechanisms. Multiple large masses, histopathologically hepatocellular adenomas and carcinomas, and hemangiosarcomas were detected in the liver samples of mice fed CDAA-HF-T(-) for 52 or 63 weeks, along with highly advanced fibrosis and numerous foamy, phagocytic macrophages in the adjacent nontumoral area. Multiple metastatic nodules were found in the lungs of one of the animals, and lymphoid clusters were found in all CDAA-HF-T(-) group mice. In the Ingenuity Pathways Analysis of RNA expression data, the CDAA-HF-T(-) feeding revealed common signal changes in nontumoral and tumoral liver tissues, including increased IL-8 and RhoGTPases signaling and decreased lipid metabolism. Meanwhile, macrophage inflammatory protein 2 (MIP-2) expression levels were upregulated in nontumoral liver tissue from the end of Week 13 of CDAA-HF-T(-) feeding to the end of Week 63. On the other hand, MIP-2 was expressed on macrophages in non-tumor areas and hepatocytes in tumor areas. Therefore, the CDAA-HF-T(-) mouse model is useful for assessing NASH and NASH-associated hepatocarcinogenesis, and IL-8 signaling plays important roles in NASH-associated carcinogenesis and cirrhosis, but it may also play different roles in nontumoral liver tissue and tumorigenesis.
非酒精性脂肪性肝炎（NASH）可进展为肝硬化，甚至肝细胞癌（HCC）。NASH 相关 HCC 的发病率正在增加，对公共健康构成严重威胁。不幸的是，包括肿瘤和非肿瘤病变之间可能存在的差异在内的潜在病理机制在很大程度上仍然未知。先前，我们报道了一种含短链脂肪酸且不含反式脂肪酸的胆碱缺乏、蛋氨酸降低、L-氨基酸定义、高脂肪饮食（CDAA-HF-T[-]）诱导的饮食性小鼠 NASH 模型，该模型可快速诱导肝脏纤维化和增生性病变。本研究旨在开发一种可评估 NASH 相关肝癌发生并鉴定其潜在机制中涉及的关键信号因子的小鼠 CDAA-HF-T(-)模型。在喂食 CDAA-HF-T(-)52 或 63 周的小鼠的肝组织样本中，检测到多个大肿块，组织病理学上为肝细胞腺瘤和癌，以及血管肉瘤，同时相邻非肿瘤区域有高度进展的纤维化和大量泡沫状、吞噬性巨噬细胞。其中一只动物的肺部发现多个转移结节，所有 CDAA-HF-T(-)组小鼠的肺部均发现淋巴样簇。在 RNA 表达数据的 Ingenuity 通路分析中，CDAA-HF-T(-)喂养显示非肿瘤和肿瘤肝组织中的共同信号变化，包括 IL-8 和 RhoGTPases 信号增加以及脂质代谢减少。同时，在 CDAA-HF-T(-)喂养结束的第 13 周至第 63 周，非肿瘤肝组织中巨噬细胞炎症蛋白 2（MIP-2）的表达水平上调。另一方面，MIP-2 在非肿瘤区域的巨噬细胞和肿瘤区域的肝细胞上表达。因此，CDAA-HF-T(-)小鼠模型可用于评估 NASH 和 NASH 相关肝癌发生，IL-8 信号在 NASH 相关致癌作用和肝硬化中起重要作用，但在非肿瘤肝组织和肿瘤发生中可能发挥不同的作用。
