Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
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DOI：
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发表时间：
2005
期刊：
影响因子：
82.9
通讯作者：
D. Cai;M. Yuan;Daniel F Frantz;P. A. Meléndez;L. Hansen;Jongsoon Lee;S. Shoelson
中科院分区：
文献类型：
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作者：
D. Cai;M. Yuan;Daniel F Frantz;P. A. Meléndez;L. Hansen;Jongsoon Lee;S. Shoelson
我们发现，NF-κ B和转录靶点在肝脏中被肥胖和高脂饮食（HFD）激活。我们通过在肝细胞中选择性表达组成型活性IKK-b，在转基因小鼠肝脏中低水平激活NF-κ B（命名为LIKK）来匹配这种慢性亚急性“炎症”状态。这些小鼠表现出2型糖尿病表型，其特征在于高血糖症、严重的肝脏胰岛素抵抗和中度全身胰岛素抵抗，包括肌肉中的影响。在LIKK小鼠中，促炎细胞因子（包括IL-6、IL-1 β和TNF-α）的肝脏产生增加的程度与野生型小鼠中HFD诱导的程度相似。在LIKK小鼠的肝脏和粘膜中观察到细胞因子信号传导的平行增加。通过全身性中和IL-6或水杨酸盐抑制IKK-β改善胰岛素抵抗。IkappaB α超阻遏物（LISR）的肝脏表达逆转了喂食HFD的LIKK小鼠和野生型小鼠的表型。这些发现表明肝脏中的脂质积累通过NF-κ B活化和下游细胞因子产生导致亚急性肝脏“炎症”。这会引起肝脏局部和全身的胰岛素抵抗。
We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.