The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1
The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1
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CREB 共激活因子 CRTC2 通过调节 SREBP1 来控制肝脏脂质代谢。
DOI：
10.1038/nature14557
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发表时间：
2015-08-13
期刊：
影响因子：
64.8
通讯作者：
Wang, Yiguo
中科院分区：
文献类型：
--
作者：
Han, Jinbo;Li, Erwei;Wang, Yiguo
肝脏中甘油三酯的异常积累，部分是由于新生脂肪生成增加，导致非酒精性脂肪性肝病和胰岛素抵抗（1,2）。甾醇调节元件结合蛋白1 （SREBP1）是一种重要的脂肪生成转录调节因子，是一种与内质网（ER）结合的非活性前体。作为对胰岛素信号的响应，SREBP1以copii依赖的方式从内质网转运到高尔基体，在高尔基体中被蛋白酶加工，然后转运到细胞核诱导脂肪生成基因表达（3-5）；然而，胰岛素抵抗型肥胖和糖尿病中SREBP1活性增强的机制尚不清楚。在这里，我们在小鼠中发现，CREB调节转录辅助激活因子2 (CRTC2)(6)作为mTOR(7)信号的介质，调节copii依赖的SREBP1加工。CRTC2与COPII复合体的一个亚基Sec23A竞争(8)，与COPII的另一个亚基Sec31A相互作用，从而破坏SREBP1的转运。在摄食过程中，mTOR磷酸化CRTC2并减弱其对copii依赖性SREBP1成熟的抑制作用。肥胖小鼠肝脏过表达mtor缺陷的CRTC2突变体改善了脂肪生成程序和胰岛素敏感性，这些结果证明了转录辅助激活因子CRTC2如何调节进食状态和肥胖中mtor介导的脂质稳态。
Abnormal accumulation of triglycerides in the liver, caused in part by increasedde novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance(1,2). Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression(3-5); however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2)(6) functions as a mediator of mTOR(7) signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex(8), to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.