Nicotinamide N-methyltransferase expression decreases in iron overload, exacerbating toxicity in mouse hepatocytes.
Nicotinamide N-methyltransferase expression decreases in iron overload, exacerbating toxicity in mouse hepatocytes.
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DOI：
10.1002/hep4.1083
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发表时间：
2017-10
影响因子：
5.1
通讯作者：
Fraenkel PG
中科院分区：
文献类型：
--
作者：
Koppe T;Patchen B;Cheng A;Bhasin M;Vulpe C;Schwartz RE;Moreno-Navarrete JM;Fernandez-Real JM;Pissios P;Fraenkel PG
铁超负荷会导致活性氧的产生，从而导致对肝脏和其他器官的持久损害。这项研究的目的是确定基因，修改铁过载的毒性。我们研究了铁超载对肝脏转录和代谢组学的影响，在小鼠模型中使用铁超载的饮食模型和遗传模型，hemojuvelin基因敲除小鼠。然后，我们评估了烟酰胺N-甲基转移酶（NNMT）表达与人类患者体内铁储备的相关性，以及NNMT敲低对原代小鼠肝细胞基因表达和活力的影响。我们发现，铁超载诱导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，NNMT是一种甲基化烟酰胺并调节肝脏葡萄糖和胆固醇代谢的酶，是遗传和饮食铁超载中肝脏中最强烈的下调基因之一。我们发现，肝脏NNMT表达与肥胖患者的血清铁蛋白水平和血清转铁蛋白饱和度呈负相关，这表明身体铁储备调节人类肝脏NNMT表达。此外，我们证明了在原代小鼠肝细胞中NNMT的腺病毒敲低加剧了铁诱导的肝细胞毒性，并增加了氧化和内质网应激的转录标志物的表达，而NNMT的过表达部分逆转了这些作用。结论：铁超载改变小鼠肝细胞中葡萄糖和烟酰胺的转录和代谢途径，并降低NNMT的表达，而NNMT缺乏则抑制铁超载的毒性作用。由于这些原因，NNMT可能是预防铁诱导的肝毒性的药物靶点。（Hepatology Communications 2017; 1：803 - 815）
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 nicotinamide N‐methyltransferase (NNMT) expression with body iron stores in human patients and the effect of NNMT 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 NNMT, 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 NNMT 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 NNMT expression. Furthermore, we demonstrated that adenoviral knockdown of NNMT in primary mouse hepatocytes exacerbates iron‐induced hepatocyte toxicity and increases expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while overexpression of NNMT partially reversed these effects. Conclusion: Iron overload alters glucose and nicotinamide transcriptional and metabolic pathways in mouse hepatocytes and decreases NNMT expression, while NNMT deficiency worsens the toxic effect of iron overload. For these reasons, NNMT may be a drug target for the prevention of iron‐induced hepatotoxicity. (Hepatology Communications 2017;1:803–815)
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影响因子：
82.9
作者：
Hong S;Moreno-Navarrete JM;Wei X;Kikukawa Y;Tzameli I;Prasad D;Lee Y;Asara JM;Fernandez-Real JM;Maratos-Flier E;Pissios P
通讯作者：
Pissios P
影响因子：
20.3
作者：
Papanikolaou, G;Tzilianos, M;Nemeth, E
通讯作者：
Nemeth, E
影响因子：
2.3
作者：
Patchen, Bonnie;Koppe, Tiago;Fraenkel, Paula G.
通讯作者：
Fraenkel, Paula G.
影响因子：
64.8
作者：
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影响因子：
15.9
作者：
Niederkofler, V;Salie, R;Arber, S
通讯作者：
Arber, S