Wunderlich F Thomas, Luedde Tom, Singer Stephan, Schmidt-Supprian Marc, Baumgartl Julia, Schirmacher Peter, Pasparakis Manolis, Brüning Jens C
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne and Center of Molecular Medicine Cologne, D-50674 Cologne, Germany.
Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1297-302. doi: 10.1073/pnas.0707849104. Epub 2008 Jan 23.
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-kappaB activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-kappaB essential modulator gene (NEMO(L-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-kappaB 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 NEMO(L-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.
肥胖相关的胰岛素抵抗和2型糖尿病的发生与肝脏中促炎途径的激活有关，导致胰岛素信号转导受损。为了进一步明确肝脏中核因子κB（NF-κB）激活在此过程中的作用，我们分析了在高脂饮食（HFD）条件下肝脏特异性失活NF-κB必需调节基因的小鼠（NEMO（L-KO）小鼠）的葡萄糖代谢情况。这些动物可免受肥胖相关胰岛素抵抗的发生，这凸显了在此背景下肝脏NF-κB激活的重要性。然而，肝脏NEMO缺乏与HFD协同作用，导致肝脏脂肪变性，其原因是过氧化物酶体增殖物激活受体（PPAR-α）表达降低和PPAR-γ表达增加。脂肪变性与炎症增加相互作用，导致这些小鼠在HFD条件下肝脏细胞凋亡增加。这些变化导致NEMO（L-KO）小鼠在正常饮食条件下发生肝脏肿瘤，当这些小鼠暴露于HFD时，这一过程会大大加剧。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过程中的相互作用。
