Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA.
Functional Genomics Laboratory, University of California, Berkeley, CA, 94720, USA.
Nat Commun. 2020 Feb 7;11(1):796. doi: 10.1038/s41467-020-14617-1.
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.
脂肪酸和甘油三酯的合成在进食和胰岛素的刺激下大大增加。这种脂肪生成的诱导涉及到脂肪生成途径中各种酶的协调转录激活，包括脂肪酸合酶和甘油-3-磷酸酰基转移酶。在这里，我们表明 JMJD1C 是肝脏中脂肪生成基因转录的特异性组蛋白去甲基酶。在进食/胰岛素的刺激下，JMJD1C 被 mTOR 复合物磷酸化在 T505 处，使其能够与 USF-1 直接相互作用，招募到脂肪生成启动子区域。因此，JMJD1C 通过去甲基化 H3K9me2 改变染色质的可及性，从而允许转录。因此，JMJD1C 在体内促进脂肪生成，增加肝脏和血浆甘油三酯水平，表明其在代谢适应中的作用，以激活进食/胰岛素反应中的脂肪生成程序，并促进脂肪变性的发展，导致胰岛素抵抗。
