Steatohepatitis/Metabolic Liver Disease
Article first published online: 8 MAR 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 55, Issue 6, pages 1727–1737, June 2012
How to Cite
Kim, K., Pyo, S. and Um, S. H. (2012), S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver. Hepatology, 55: 1727–1737. doi: 10.1002/hep.25537
Potential conflict of interest: Nothing to report.
These studies were supported by a National Research Foundation grant of Korea (2010-0010978) funded by the Ministry of Education, Science, and Technology, a grant of the Korea Healthcare Technology Research and Development Project, Ministry for Health, Welfare, and Family Affairs, Korea (A101218), Samsung Biomedical Research Institute (B-A9-008-3), and the promotional program for the core faculty of Sungkyunkwan University. S.H.U. is the recipient of a POSCO T.J. Park junior faculty fellowship, and K.K is the recipient of the BK21 postdoctoral fellowship.
- Issue published online: 29 MAY 2012
- Article first published online: 8 MAR 2012
- Accepted manuscript online: 20 DEC 2011 04:47AM EST
- Manuscript Accepted: 4 DEC 2011
- Manuscript Received: 22 AUG 2011
Nutrient homeostasis is tightly regulated by the balance between energy production and utilization. During fasting, production of ketone bodies as an alternative energy source is critical to maintain nutrient homeostasis. An important component in the nutrient-sensitive signaling pathway is S6 kinase 2 (S6K2), a downstream effector of mammalian target of rapamycin. Here, we show that mice lacking S6K2 exhibit elevated levels of ketone bodies and enhanced peroxisome proliferator-activated receptor alpha (PPARα) activity upon nutrient availability. Consistent with this, knockdown of S6K2 increases the transcriptional activity of PPARα. S6K2 suppresses PPARα by associating with its corepressor, nuclear receptor corepressor 1 (NCoR1), and by inducing the recruitment of NCoR1 to the nucleus. Moreover, ob/ob mice, a genetic model of obesity, have markedly elevated S6K2 activity, and S6K2 was strongly associated with NCoR1 in the nucleus of liver cells. Conclusion: Our findings suggest that S6K2 regulates hepatic energy homeostasis by repressing PPARα activity and point to its potential relevance for therapeutic strategies designed to modulate S6K2 activity as a treatment for deregulated ketone body production. (HEPATOLOGY 2012;55:1727–1737)