A maternal high-fat diet induces fetal origins of NASH-HCC in mice. A maternal high-fat diet induces fetal origins of NASH-HCC in mice

Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC. Overall design: Comaprison between fetal livers from HFD-fed dams and those from CD-fed dams. There are two biological replicates for each conditions.

母体营养过剩可影响子代罹患非酒精性脂肪性肝炎（NASH）的易感性。高脂饮食（HFD）喂养的母鼠所产雄性子代可发展为重症NASH，进而形成高血管化肿瘤。癌-睾丸抗原HORMA结构域包含蛋白1（HORMAD1）是高脂饮食母鼠胎肝中146个上调差异表达基因之一；在15周龄高脂饮食母鼠子代的肝母细胞以及NASH相关性肝细胞癌（HCC）组织中，HORMAD1与缺氧诱导因子1α（HIF-1α）均呈现过表达状态。缺氧可显著上调原代小鼠肝细胞中Hormad1的表达水平。尽管小鼠Hormad1基因内存在3个潜在的缺氧反应元件，但Hif-1α小干扰RNA（siRNA）仅能小幅降低缺氧诱导的Hormad1 mRNA表达水平。与之相反，N-乙酰半胱氨酸可抑制缺氧诱导的Hormad1表达，而鱼藤酮无此效应，这表明Hormad1的表达依赖于非线粒体活性氧的产生。对高脂饮食母鼠的胎鼠开展同步辐射相衬显微计算机断层扫描（同步辐射相衬微CT）结果显示，其胎肝显著肿大，而脐静脉尺寸未发生明显变化，这可能会引发胎肝缺氧。基于上述研究结果，母体高脂饮食可通过缺氧途径诱导NASH/HCC的胎源性发生，且HORMAD1可作为NASH/HCC的潜在治疗靶点。整体实验设计：对比高脂饮食母鼠与普通饲料（CD）喂养母鼠的胎肝组织，每组设置2个生物学重复。