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首页> 外文期刊>Cell metabolism >Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones.
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Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones.

机译：肝脏中ARNT / HIF1beta的切除会改变糖异生，脂肪形成基因表达和血清酮。

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摘要

We have previously shown that expression of the transcription factor ARNT/HIF1beta is reduced in islets of humans with type 2 diabetes. We have now found that ARNT is also reduced in livers of diabetics. To study the functional effect of its reduction, we created mice with liver-specific ablation (L-ARNT KO) using ARNT loxP mice and adenoviral-mediated delivery of Cre. L-ARNT KO mice had normal blood glucose but increased fed insulin levels. These mice also exhibited features of type 2 diabetes with increased hepatic gluconeogenesis, increased lipogenic gene expression, and low serum beta-hydroxybutyrate. These effects appear to be secondary to increased expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha), farnesoid X receptor (FXR), and sterol response element-binding protein 1c (SREBP-1c) and a reduction in phosphorylation of AMPK without changes in the expression of enzymes in ketogenesis, fatty acid oxidation, or FGF21. These results demonstrate that a deficiency of ARNT action in the liver, coupled with that in beta cells, could contribute to the metabolic phenotype of human type 2 diabetes.
机译：我们先前已经表明，在患有2型糖尿病的人类胰岛中，转录因子ARNT / HIF1beta的表达降低了。现在我们发现糖尿病人肝脏中的ARNT也降低了。为了研究其减少的功能效果，我们使用ARNT loxP小鼠和腺病毒介导的Cre产生了具有肝脏特异性消融（L-ARNT KO）的小鼠。 L-ARNT KO小鼠血糖正常，但进食胰岛素水平升高。这些小鼠还表现出2型糖尿病的特征，即肝糖异生增加，脂肪基因表达增加和血清β-羟基丁酸酯含量低。这些作用似乎是继CCAAT /增强子结合蛋白α（C / EBPalpha），法呢类X受体（FXR）和固醇反应元件结合蛋白1c（SREBP-1c）表达增加以及AMPK磷酸化降低之后的继发效应在生酮，脂肪酸氧化或FGF21中酶的表达没有变化。这些结果表明，肝脏中ARNT作用的缺乏以及β细胞中的缺乏，可能导致人类2型糖尿病的代谢表型。

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