S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver
S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver
复制标题
DOI：
10.1002/hep.25537
复制
发表时间：
2012-06-01
期刊：
影响因子：
13.5
通讯作者：
Um, Sung Hee
中科院分区：
文献类型：
--
作者：
Kim, KyeongJin;Pyo, Suhkneung;Um, Sung Hee
营养物质的体内平衡受到能量生产和利用之间的平衡的严格调节。在禁食期间，酮体作为替代能源的产生对于维持营养平衡至关重要。营养敏感性信号传导途径中的一个重要组分是S6激酶2（S6 K2），其是雷帕霉素的哺乳动物靶标的下游效应物。在这里，我们表明，缺乏S6 K2的小鼠表现出升高的酮体水平和增强的过氧化物酶体增殖物激活受体α（PPARa）活性后，营养的可用性。与此一致，S6 K2的敲低增加了PPARa的转录活性。S6 K2通过与其辅阻遏物核受体辅阻遏物1（NCoR 1）结合并诱导NCoR 1募集至细胞核来抑制PPARa。此外，肥胖的遗传模型ob/ob小鼠具有显著升高的S6 K2活性，并且S6 K2与肝细胞核中的NCoR 1强烈相关。结论：我们的研究结果表明，S6 K2通过抑制PPARa活性来调节肝脏能量稳态，并指出其与旨在调节S6 K2活性的治疗策略的潜在相关性，作为对酮体产生失调的治疗。（肝脏学2012;55：17271737）
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 (PPARa) activity upon nutrient availability. Consistent with this, knockdown of S6K2 increases the transcriptional activity of PPARa. S6K2 suppresses PPARa 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 PPARa 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;55:17271737)