Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis

被引:91
|
作者
Wunderlich, F. Thomas [1 ]
Luedde, Tom [2 ,3 ]
Singer, Stephan
Schmidt-Supprian, Marc [5 ]
Baumgartl, Julia [1 ]
Schirmacher, Peter [4 ]
Pasparakis, Manolis [2 ,3 ]
Bruening, Jens C. [1 ]
机构
[1] Univ Cologne, Ctr Mol Med, Inst Genet, Dept Mouse Genet & Metab, D-50674 Cologne, Germany
[2] Univ Cologne, Inst Genet, Dept Mouse Genet & Inflammat, D-50674 Cologne, Germany
[3] European Mol Biol Lab, Mouse Biol Unit, I-000016 Monterotondo, Italy
[4] Heidelberg Univ, Inst Pathol, Heidelberg, Germany
[5] Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA
关键词
insulin sensitivity; spontaneous hepatic carcinoma; steatosis; hepatic NEMO deficiency;
D O I
10.1073/pnas.0707849104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1297 / 1302
页数:6
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