MED17 is Phosphorylated at S53 by CK2 for Transcriptional Activation of Lipogenic Genes in Response to Insulin

Abstract

De novo lipogenesis is under tight regulation by nutritional status and hormonal conditions. Many of the enzymes involved in this process, such as fatty acid synthase (FASN), are regulated at the transcriptional level by insulin signaling cascades. We previously showed that USF1 is a key transcription factor for FASN activation that, by binding to the −65 E‐box, leads to the recruitment of various other lipogenic transcription factors for insulin mediated transcriptional activation. We show here that USF1 directly interacts with the Mediator subunit MED17 at the FASN promoter for recruitment of the Mediator complex, as well as POL II and other general transcription machinery. Additionally, we show that MED17 is phosphorylated at S53 by casein kinase 2 (CK2) in the livers of fed mice or insulin‐stimulated hepatocytes, but not in the livers of fasted mice or untreated hepatocytes, and that this phosphorylation event is required for the FASN promoter activation in response to insulin. To assess whether this newly identified pathway becomes dysregulated in obesity, we next examined phosphorylation of MED17 in the liver of leptin‐deficient and insulin resistant ob/ob mice and, indeed, we detected chronic phosphorylation of S53 even in livers of fasted mice. These results demonstrate that phosphorylation of MED17 at S53 by CK2 is required for the transcriptional activation of lipogenic genes in response to insulin, and furthermore, that dysregulation of this pathway may contribute to the chronic activation of lipogenesis for insulin resistance.Support or Funding InformationRO1DK081098 (NIH)F32DK105671 (NIH)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.