Research ArticleMetabolism

Transcriptional activation of lipogenesis by insulin requires phosphorylation of MED17 by CK2

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Science Signaling  21 Feb 2017:
Vol. 10, Issue 467, eaai8596
DOI: 10.1126/scisignal.aai8596

Linking insulin to lipogenesis through MED17

Food intake stimulates the release of insulin, which triggers various anabolic processes including lipogenesis in the liver. Viscarra et al. found that insulin stimulation in hepatocytes or feeding in mice triggered the phosphorylation of the transcriptional coactivator MED17, which enabled the transcription factor USF1 to activate genes encoding lipogenic factors. This phosphorylation event, which was mediated by the kinase CK2, occurred only if MED17 was not previously phosphorylated by p38, a kinase that is activated by fasting. Knockdown of CK2 or administration of a CK2 inhibitor reduced lipogenesis and triglyceride content in the livers of mice. Inappropriate accumulation of fatty acids in the liver, a condition called hepatic steatosis, can lead to hepatic dysfunction and cancer, suggesting that CK2 or other components in this pathway could be targeted to prevent this common metabolic condition.


De novo lipogenesis is precisely regulated by nutritional and hormonal conditions. The genes encoding various enzymes involved in this process, such as fatty acid synthase (FASN), are transcriptionally activated in response to insulin. We showed that USF1, a key transcription factor for FASN activation, directly interacted with the Mediator subunit MED17 at the FASN promoter. This interaction recruited Mediator, which can bring POL II and other general transcription machinery to the complex. Moreover, we showed that MED17 was phosphorylated at Ser53 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. Furthermore, activation of the FASN promoter in response to insulin required this CK2-mediated phosphorylation event, which occurred only in the absence of p38 MAPK–mediated phosphorylation at Thr570. Overexpression of a nonphosphorylatable S53A MED17 mutant or knockdown of MED17, as well as CK2 knockdown or inhibition, impaired hepatic de novo fatty acid synthesis and decreased triglyceride content in mice. These results demonstrate that CK2-mediated phosphorylation of Ser53 in MED17 is required for the transcriptional activation of lipogenic genes in response to insulin.

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