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Enhanced insulin signaling and its downstream effects in iron-overloaded primary hepatocytes from hepcidin knock-out mice.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.bbamcr.2019.118621 Jithu V James 1 , Joe Varghese 1 , Andrew T Mckie 2 , Sophie Vaulont 3 , Molly Jacob 1
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2019-12-05 , DOI: 10.1016/j.bbamcr.2019.118621 Jithu V James 1 , Joe Varghese 1 , Andrew T Mckie 2 , Sophie Vaulont 3 , Molly Jacob 1
Affiliation
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BACKGROUND
Increased body iron stores have been implicated in the pathogenesis of diabetes mellitus. However, the molecular mechanisms involved are unclear. The liver plays a central role in homeostasis of iron and glucose in the body. Mice deficient in hepcidin (the central regulator of systemic iron homeostasis) (Hamp1-/- mice) accumulate iron in the liver in vivo. The effects of such iron loading on hepatic insulin signaling and glucose metabolism are not known.
METHODS
Hepatocytes isolated from Hamp1-/- mice were studied for markers of insulin signaling (and its downstream effects), glucose production, expression of gluconeogenic and lipogenic enzymes, and markers of AMPK (AMP-activated protein kinase) activation and oxidative stress. These parameters were studied both in the absence and presence of insulin, and also with the use of an iron chelator.
RESULTS
Akt in the insulin signaling pathway was found to be activated in the Hamp1-/- hepatocytes to a greater extent than wild-type (WT) cells, both under basal conditions and in response to insulin. Incubation of the Hamp1-/- hepatocytes with an iron chelator attenuated these effects. There was no evidence of oxidative stress or AMPK activation in the Hamp1-/- hepatocytes. Glucose production by these cells was similar to that by WT cells. Gene expression of key gluconeogenic enzymes was decreased in these cells. In addition, they showed evidence of increased lipogenesis.
CONCLUSIONS
Hepatocytes from Hamp1-/- mice showed evidence of greater sensitivity to the effects of insulin than WT hepatocytes. This may explain the insulin-sensitive phenotype that has been reported in classical hemochromatosis.
中文翻译：
从铁调素基因敲除小鼠中铁超负荷的原代肝细胞中增强的胰岛素信号传导及其下游效应。
背景技术体内铁储备的增加已经与糖尿病的发病机理有关。但是，涉及的分子机制尚不清楚。肝脏在体内铁和葡萄糖的体内平衡中起着核心作用。缺乏铁调素（全身铁稳态的中央调节剂）的小鼠（Hamp1-/-小鼠）体内的铁蓄积在肝脏中。这种铁负载对肝胰岛素信号传导和葡萄糖代谢的影响尚不清楚。方法研究了从Hamp1-/-小鼠分离的肝细胞的胰岛素信号（及其下游作用）标记，葡萄糖生成，糖原异生和脂肪生成酶的表达以及AMPK（AMP激活的蛋白激酶）活化和氧化应激的标志。在不存在和存在胰岛素的情况下都对这些参数进行了研究，以及使用铁螯合剂。结果发现在基础条件下和对胰岛素的反应中，胰岛素信号通路中的Akt在Hamp1-/-肝细胞中的活化程度均高于野生型（WT）细胞。将Hamp1-/-肝细胞与铁螯合剂一起孵育可减弱这些作用。在Hamp1-/-肝细胞中没有氧化应激或AMPK活化的证据。这些细胞产生的葡萄糖与野生型细胞产生的葡萄糖相似。这些细胞中关键糖异生酶的基因表达降低。此外，他们显示出脂肪形成增加的证据。结论来自Hamp1-/-小鼠的肝细胞显示出比WT肝细胞对胰岛素作用更敏感的证据。这可以解释经典血色素沉着病中已报道的胰岛素敏感性表型。
更新日期：2019-12-05
中文翻译：
从铁调素基因敲除小鼠中铁超负荷的原代肝细胞中增强的胰岛素信号传导及其下游效应。
背景技术体内铁储备的增加已经与糖尿病的发病机理有关。但是，涉及的分子机制尚不清楚。肝脏在体内铁和葡萄糖的体内平衡中起着核心作用。缺乏铁调素（全身铁稳态的中央调节剂）的小鼠（Hamp1-/-小鼠）体内的铁蓄积在肝脏中。这种铁负载对肝胰岛素信号传导和葡萄糖代谢的影响尚不清楚。方法研究了从Hamp1-/-小鼠分离的肝细胞的胰岛素信号（及其下游作用）标记，葡萄糖生成，糖原异生和脂肪生成酶的表达以及AMPK（AMP激活的蛋白激酶）活化和氧化应激的标志。在不存在和存在胰岛素的情况下都对这些参数进行了研究，以及使用铁螯合剂。结果发现在基础条件下和对胰岛素的反应中，胰岛素信号通路中的Akt在Hamp1-/-肝细胞中的活化程度均高于野生型（WT）细胞。将Hamp1-/-肝细胞与铁螯合剂一起孵育可减弱这些作用。在Hamp1-/-肝细胞中没有氧化应激或AMPK活化的证据。这些细胞产生的葡萄糖与野生型细胞产生的葡萄糖相似。这些细胞中关键糖异生酶的基因表达降低。此外，他们显示出脂肪形成增加的证据。结论来自Hamp1-/-小鼠的肝细胞显示出比WT肝细胞对胰岛素作用更敏感的证据。这可以解释经典血色素沉着病中已报道的胰岛素敏感性表型。
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