近日，著名国际学术期刊Nature 在线发表了清华大学王一国研究员领导的研究小组关于肝脏脂代谢调控机制的最新研究进展。

　　众所周知，肝脏在脂类的消化、吸收、分解、合成及运输等代谢过程中均起重要作用。肝脏是脂肪酸氧化分解以及脂肪酸和脂肪合成的重要场所，但因脂质从头合成过程增强使得甘油三酯在肝脏异常积累，导致非酒精性脂肪肝和胰岛素抵抗情况的发生。

　　SREBP1是脂质合成过程中一个非常重要的转录调控因子，该基因在经过转录翻译后以非活性状态的前体形式与内质网发生结合，当细胞受到胰岛素信号激活，SREBP1会以COPII依赖性途径从内质网转运到高尔基体，经过高尔基体内部蛋白酶的加工形成活性形式，随后发生核质穿梭转移到细胞核中诱导脂质合成基因的表达。但一直以来，在胰岛素抵抗的肥胖和188bet在线平台网址 中，SREBP1的活性如何得到增强，其中的机制一直不清楚。

　　在这项研究中，研究人员发现CREB转录调控共激活因子2（CRTC2）能够调节COPII依赖性的SREBP1加工过程，同时CRTC2的这一作用还会受到mTOR信号途径的调控。研究人员发现CRTC2能够与COPII复合体中的一个重要组分竞争结合该复合体中另一组分，从而扰乱SREBP1的转运。在进食过程中，mTOR能够对CRTC2进行磷酸化，减弱其对COPII依赖性SREBP1加工途径的抑制性作用。在肥胖小鼠的肝脏中过表达不能被mTOR磷酸化的CRTC2突变体能够显着改变脂质合成基因的表达，提高胰岛素敏感性。

　　综上所述，这项研究发现CRTC2能够通过影响COPII依赖性的SREBP1蛋白加工过程抑制脂质合成，同时CRTC2还会受到mTOR信号途径的调控，这一发现为改善非酒精性脂肪肝，开发相关干预治疗手段提供了重要理论基础。

　　doi:10.1038/nature14557

　　The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1

　　Jinbo Han,Erwei Li,Liqun Chen,Yuanyuan Zhang,Fangchao Wei,Jieyuan Liu,Haiteng Deng &Yiguo Wang

　　Abnormal accumulation of triglycerides in the liver, caused in part by increased de novolipogenesis, results in non-alcoholic fatty liver disease and insulin resistance1, 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 expression3, 4, 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 mTOR7 signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex8, 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.