Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells
Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells
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DOI：
10.1093/jn/137.11.2366
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发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Sharp, Paul
中科院分区：
文献类型：
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作者：
Chung, Bomee;Matak, Pavle;Sharp, Paul
肥胖是一个主要的全球性健康问题，与低度炎症有关，在许多情况下，与缺铁状态有关。我们推测，脂肪因子瘦素可能在调节超重人群的铁代谢中发挥作用，因为它与IL-6具有许多共同的生物学特征，IL-6是慢性疾病贫血发展的主要因素，通过刺激铁调节激素hepcidin的产生和释放。为了验证这一假设，我们将HuH 7人肝癌细胞暴露于瘦素，并通过定量PCR测量hepcidin mRNA的表达。HuH 7细胞也用铁调素启动子-荧光素酶报告基因构建体转染以研究铁调素的转录调控。在瘦素处理的细胞中，hepcidin mRNA表达显著增强。用Janus激酶（JAK）2抑制剂预孵育显著降低了这种反应。铁调素启动子活性也增加了瘦素的存在下。这种效果被降低的突变的信号转导和转录激活因子（STAT）3结合基序的铁调素启动子或共表达显性负STAT 3突变体。这些数据表明，瘦素通过JAK 2/STAT 3信号通路上调肝hepcidin的表达。因此，超重个体中瘦素的产生增加可能是这些人群中观察到的异常铁状态的主要原因。
Obesity is a major global health problem and is associated with low-grade inflammation and, in a number of cases, poor iron status. We speculated that the adipokine leptin might play a role in regulating iron metabolism in the overweight population because it shares a number of common biological features with IL-6, a major factor in the development of the anemia of chronic disease via its stimulatory actions on the production and release of the iron regulatory hormone hepcidin. To test this hypothesis, we exposed HuH7 human hepatoma cells to leptin and measured hepcidin mRNA expression by quantitative PCR. HuH7 cells were also transfected with a hepcidin promoter-luciferase reporter gene construct to investigate transcriptional regulation of hepcidin. In leptin-treated cells, hepcidin mRNA expression was enhanced significantly. Preincubation with a Janus kinase (JAK) 2 inhibitor significantly diminished this response. Hepcidin promoter activity was also increased in the presence of leptin. This effect was decreased either by mutation of the signal transducer and activator of transcription (STAT) 3 binding motif in the hepcidin promoter or by coexpressing a dominant-negative STAT3 mutant. These data suggest that leptin upregulates hepatic hepcidin expression through the JAK2/STAT3 signaling pathway. As a consequence, the increased production of leptin in overweight individuals might be a major contributor to the aberrant iron status observed in these population groups.