Abstract
Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.
Highlights
Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin
We tested other Transcription factors (TF) that are known to regulate lipogenesis, SREBP-1c, LXR, and ChREBP. None of these TFs directly interacted with JMJD1C, SREBP-1c and LXR could make a complex with JMJD1C indirectly (Supplementary Fig. 1a, b)
These results demonstrate the direct interaction of JMJD1C with USF-1 for lipogenic gene transcription
Summary
Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance. We found that a Mediator component, MED17 is phosphorylated by CK2 to be recruited by USF-1, linking USF-1 to the preinitiation complex formation for transcription[8] This common mechanism governs transcription of FAS but a battery of other lipogenic genes to fine-tune the rate of lipogenesis[4,9,10,11]
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