Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
Am J Physiol Endocrinol Metab. 2011 Mar;300(3):E500-7. doi: 10.1152/ajpendo.00225.2010. Epub 2010 Dec 14.
It has previously been known that transcription of the PGC-1α gene can be either inhibited or stimulated by p38 MAP kinase (p38 MAPK). To determine whether p38 MAPK plays an inhibitory or stimulatory role in PGC-1α gene transcription, we further investigated the role of p38 MAPK in this study. Our results showed that the basal level of p38 MAPK phosphorylation was increased in gastrocnemius of mice under HFD and that p38 MAPK stimulated PGC-1α gene transcription in C(2)C(12) myotubes. Our results also provided new mechanisms in myotubes that the p38 MAPK-induced PGC-1α gene transcription was mediated by CREB. In exploring the role of the Akt-dependent insulin signaling on PGC-1α gene transcription, we found that the basal Akt-dependent signaling was increased in gastrocnemius of mice under HFD. The p38 MAPK-induced PGC-1α gene transcription was prevented by insulin. Insulin suppression of PGC-1α gene transcription was neutralized by overexpression of the constitutively nuclear form of FoxO1. Finally, we located three insulin response elements (IREs) in the PGC-1α promoter, and mutations of these IREs abolish or blunt activity of the PGC-1α promoter. Together, our results show that transcription of the PGC-1α gene is balanced by different intracellular signaling pathways.
先前已知，p38 MAP 激酶（p38 MAPK）可以抑制或刺激 PGC-1α 基因的转录。为了确定 p38 MAPK 在 PGC-1α 基因转录中是否发挥抑制或刺激作用，我们在本研究中进一步研究了 p38 MAPK 的作用。我们的结果表明，高脂肪饮食（HFD）下的小鼠比目鱼肌中 p38 MAPK 磷酸化的基础水平增加，并且 p38 MAPK 刺激 C(2)C(12)肌管中的 PGC-1α 基因转录。我们的结果还在肌管中提供了新的机制，即 p38 MAPK 诱导的 PGC-1α 基因转录是由 CREB 介导的。在探索 Akt 依赖性胰岛素信号对 PGC-1α 基因转录的作用时，我们发现高脂肪饮食（HFD）下的小鼠比目鱼肌中的基础 Akt 依赖性信号增加。胰岛素可抑制 PGC-1α 基因转录，而胰岛素对 PGC-1α 基因转录的抑制作用可被 FoxO1 的组成性核形式的过表达中和。最后，我们在 PGC-1α 启动子中定位了三个胰岛素反应元件（IRE），这些 IRE 的突变会使 PGC-1α 启动子的活性丧失或变钝。总之，我们的结果表明，PGC-1α 基因的转录受到不同的细胞内信号通路的平衡调节。
