Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis
Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis
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DOI：
10.1073/pnas.0707849104
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发表时间：
2008-01-29
影响因子：
11.1
通讯作者：
Bruening, Jens C.
中科院分区：
文献类型：
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作者：
Wunderlich, F. Thomas;Luedde, Tom;Bruening, Jens C.
肥胖相关的胰岛素抵抗和2型糖尿病的发展与肝脏中促炎途径的激活有关，导致胰岛素信号转导受损。为了进一步确定肝脏NF-κ B激活在这一过程中的作用，我们分析了暴露于高脂饮食（HFD）的NF-κ B必需调节基因肝脏特异性失活小鼠（NEMOL-KO小鼠）的葡萄糖代谢。这些动物被保护免于肥胖相关的胰岛素抵抗的发展，突出了肝NF-κ B活化在这种情况下的重要性。然而，由于过氧化物酶体增殖物激活受体（PPAR-alpha）降低和PPAR-gamma表达增加，肝脏NEMO缺乏与HFD在肝脏脂肪变性的发展中协同作用。脂肪变性与增加的炎症相互作用，导致HFD下这些小鼠肝脏中的细胞凋亡增加。这些变化导致NEMOL-KO小鼠在正常饮食下的肝脏肿瘤发生，当这些小鼠暴露于HFD时，该过程在很大程度上加重。这些数据直接证明了肝脏炎症、饮食组成和代谢在肝脏肿瘤发生发展中的相互作用。
Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-kappa B activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-kappa B essential modulator gene (NEMOL-KO mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-kappa B activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-alpha) and increased PPAR-gamma expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMOL-KO mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis.