Koppe Tiago, Patchen Bonnie, Cheng Aaron, Bhasin Manoj, Vulpe Chris, Schwartz Robert E, Moreno-Navarrete Jose Maria, Fernandez-Real Jose Manuel, Pissios Pavlos, Fraenkel Paula G
Division of Hematology/Oncology.
Cancer Research Institute, Beth Israel Deaconess Medical Center Boston MA.
Hepatol Commun. 2017 Sep 11;1(8):803-815. doi: 10.1002/hep4.1083. eCollection 2017 Oct.
Iron overload causes the generation of reactive oxygen species that can lead to lasting damage to the liver and other organs. The goal of this study was to identify genes that modify the toxicity of iron overload. We studied the effect of iron overload on the hepatic transcriptional and metabolomic profile in mouse models using a dietary model of iron overload and a genetic model, the hemojuvelin knockout mouse. We then evaluated the correlation of expression with body iron stores in human patients and the effect of knockdown on gene expression and viability in primary mouse hepatocytes. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism and that , an enzyme that methylates nicotinamide and regulates hepatic glucose and cholesterol metabolism, is one of the most strongly down-regulated genes in the liver in both genetic and dietary iron overload. We found that hepatic expression is inversely correlated with serum ferritin levels and serum transferrin saturation in patients who are obese, suggesting that body iron stores regulate human liver expression. Furthermore, we demonstrated that adenoviral knockdown of in primary mouse hepatocytes exacerbates iron-induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of partially reversed these effects. : Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases expression, while deficiency worsens the toxic effect of iron overload. For these reasons, may be a drug target for the prevention of iron-induced hepatotoxicity. ( 2017;1:803-815).
铁过载会导致活性氧的产生，进而对肝脏和其他器官造成永久性损伤。本研究的目的是鉴定能够改变铁过载毒性的基因。我们使用铁过载饮食模型和遗传模型（血色素沉着症相关蛋白基因敲除小鼠），研究了铁过载对小鼠模型肝脏转录组和代谢组谱的影响。然后，我们评估了人类患者中基因表达与体内铁储存的相关性，以及基因敲低对原代小鼠肝细胞基因表达和活力的影响。我们发现，铁过载诱导了参与葡萄糖和烟酰胺代谢的基因和代谢物表达的显著变化，并且一种对烟酰胺进行甲基化并调节肝脏葡萄糖和胆固醇代谢的酶，在遗传性和饮食性铁过载的肝脏中都是下调最显著的基因之一。我们发现，肥胖患者肝脏中的该基因表达与血清铁蛋白水平和血清转铁蛋白饱和度呈负相关，这表明体内铁储存调节人类肝脏中的该基因表达。此外，我们证明，在原代小鼠肝细胞中通过腺病毒介导敲低该基因会加剧铁诱导的肝细胞毒性，并增加氧化应激和内质网应激转录标志物的表达，而该基因的过表达则部分逆转了这些效应。结论：铁过载改变了小鼠肝细胞中葡萄糖和烟酰胺的转录及代谢途径，并降低了该基因的表达，而该基因的缺失会加重铁过载的毒性作用。基于这些原因，该基因可能是预防铁诱导肝毒性的药物靶点。（《》2017年；第1期：803 - 815页） （注：原文中部分内容缺失英文具体信息，翻译时用“《》”标注）
