Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway
Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway
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DOI：
10.2337/db15-0242
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发表时间：
2015-10-01
期刊：
影响因子：
7.7
通讯作者：
Ye, Jianping
中科院分区：
文献类型：
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作者：
Ke, Bilun;Zhao, Zhiyun;Ye, Jianping
转录因子核因子-kappaB(NF-kappa B)介导细胞内的炎症和应激信号。为了验证核因子-kappa B在控制肝脏胰岛素敏感性中的作用，我们通过缺失p65基因使C57BL/6小鼠肝脏中的核因子-kappaB失活，这是通过杂交Floxed-p65和Alb-cre小鼠产生的L-p65基因敲除(KO)小鼠实现的。在饮食期间，KO小鼠在生长、繁殖和体重方面没有表现出任何变化。然而，高脂饮食(HFD)的小鼠表现出全身胰岛素敏感性的改善。肝脏对胰岛素的敏感性增强，表现为丙酮酸耐受性增加，Akt磷酸化，肝脏糖异生基因表达减少。在肝脏中，细胞内cAMP减少，CREB磷酸化降低。环核苷酸磷酸二酯酶-3B(PDE3B)是一种cAMP降解酶，由于缺乏核因子-kappaB的活性，其在mRNA和蛋白水平上均增加。核因子-kappaB通过基因启动子上的三个DNA结合位点抑制肿瘤坏死因子-α对PDE3B的转录。服用HFD的KO小鼠的身体成分、食物摄入量、能量消耗以及全身和肝脏炎症没有明显改变。这些数据表明，核因子-kappaB通过抑制PDE3B基因转录上调cAMP来抑制肝脏胰岛素敏感性。
The transcription factor nuclear factor-kappa B (NF-kappa B) mediates inflammation and stress signals in cells. To test NF-kappa B in the control of hepatic insulin sensitivity, we inactivated NF-kappa B in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-kappa B activity. NF-kappa B was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-alpha. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-kappa B inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.