These authors contributed equally to this work.
Steatohepatitis/Metabolic Liver Disease
Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice
Article first published online: 25 JUN 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 2, pages 603–616, August 2013
How to Cite
Wang, X.-A., Zhang, R., Jiang, D., Deng, W., Zhang, S., Deng, S., Zhong, J., Wang, T., Zhu, L.-H., Yang, L., Hong, S., Guo, S., Chen, K., Zhang, X.-F., She, Z., Chen, Y., Yang, Q., Zhang, X.-D. and Li, H. (2013), Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice. Hepatology, 58: 603–616. doi: 10.1002/hep.26368
Potential conflict of interest: Nothing to report.
Supported by grants from the National Natural Science Foundation of China (grant nos.: 81170086 and 81000342), the National Science and Technology Support Project (grant nos.: 2011BAI15B02 and 2012BAI39B05), the National Basic Research Program of China (grant no.: 2011CB503902), and the Special National Major Drug Discovery (2011ZX09307-302).
- Issue published online: 29 JUL 2013
- Article first published online: 25 JUN 2013
- Accepted manuscript online: 7 MAR 2013 12:05PM EST
- Manuscript Accepted: 25 FEB 2013
- Manuscript Revised: 21 FEB 2013
- Manuscript Received: 28 SEP 2012
Obesity is a calorie-excessive state associated with high risk of diabetes, atherosclerosis, and certain types of tumors. Obesity may induce inflammation and insulin resistance (IR). We found that the expression of interferon (IFN) regulatory factor 9 (IRF9), a major transcription factor mediating IFN responses, was lower in livers of obese mice than in those of their lean counterparts. Furthermore, whole-body IRF9 knockout (KO) mice were more obese and had aggravated IR, hepatic steatosis, and inflammation after chronic high-fat diet feeding. In contrast, adenoviral-mediated hepatic IRF9 overexpression in both diet-induced and genetically (ob/ob) obese mice showed markedly improved hepatic insulin sensitivity and attenuated hepatic steatosis and inflammation. We further employed a yeast two-hybrid screening system to investigate the interactions between IRF9 and its cofactors. Importantly, we identified that IRF9 interacts with peroxisome proliferator-activated receptor alpha (PPAR-α), an important metabolism-associated nuclear receptor, to activate PPAR-α target genes. In addition, liver-specific PPAR-α overexpression rescued insulin sensitivity and ameliorated hepatic steatosis and inflammation in IRF9 KO mice. Conclusion: IRF9 attenuates hepatic IR, steatosis, and inflammation through interaction with PPAR-α. (Hepatology 2013;58:603–616)