Glutamine-released ammonia acts as an unprecedented signaling molecule activating lipid production.
Glutamine-released ammonia acts as an unprecedented signaling molecule activating lipid production.
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DOI：
10.1016/j.gendis.2022.07.017
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发表时间：
2023-03
期刊：
影响因子：
6.8
通讯作者：
Guo, Deliang
中科院分区：
文献类型：
--
作者：
Cheng, Chunming;Kelsey, Scott;Guo, Deliang
在健康的人体中，氨在血液循环中的浓度约为11e32 mmol/L，直到最近发表在《自然代谢》上的一篇报告才知道氨是否起到了任何生理作用。1氨，长期以来被认为是氨基酸代谢的有毒废物，需要以尿素的形式从人体排泄出来。有趣的是，在这篇论文中，程等人首次报道了氨不是一种废物；相反，它是一种前所未有的信号分子，将葡萄糖和谷氨酰胺与人类细胞中的脂肪产生联系在一起。这项研究表明，谷氨酰胺释放的氨触发了一系列细胞过程，导致脂肪生成机制的激活，从而产生脂肪(图1)。这一发现对开发治疗癌症和代谢综合征等人类疾病具有重要意义，因为代谢失调是这些疾病的标志。在真核细胞中，脂肪合成主要由固醇调节元件结合蛋白(SREBPs)调节，SREBPs是一个转录因子家族，包含SREBP-1a、-1c和-2。2、3合成后，SREBP前体(W125kD)与内质网(ER)膜结合，与SREBP裂解激活蛋白(SCAP)和胰岛素诱导基因蛋白(Insig)形成复合体，包括Insig-1和Insig-2(ER驻留蛋白)。脂类是细胞膜的基本成分，而过量的脂类，如脂肪酸和胆固醇，会对细胞造成毒性。因此，SREBP的转录活性和脂质生成率受到严格控制。SREBPs首先需要离开内质网，移位到高尔基体，被两种蛋白酶(S1P和S2P)连续切割，释放活性的N端SREBP形式(W65kD)进入细胞核，激活成脂基因的表达。2、3控制SREBPs退出内质网的关键步骤是受SCAP的调控，SCAP与包被COPII的囊泡结合，将SREBPs从内质网运输到高尔基体。然而，这一步骤受到内质网驻留蛋白Insig的限制，它直接与SCAP结合，阻止其与COPII蛋白相互作用，从而在空间上将SCAP/SREBP复合体限制在内质网。因此，SREBP激活的关键步骤是SCAP摆脱Insig结合。2015年前，对SCAP/的理解
In healthy humans, ammonia circulates in the bloodstream at a concentration around 11e32 mmol/L. Whether ammonia plays any physiological role has been unknown until a recent report published in Nature Metabolism. 1 Ammonia, long thought to be a toxic waste product of amino acid metabolism, needs to be excreted from the human body as urea. Intriguingly, in this paper, Cheng et al 1 for the first time reported that ammonia is not a waste product; rather, it is an unprecedented signaling molecule tying glucose and glutamine to lipid production in human cells. This study revealed that ammonia released from glutamine triggers a cascade of cellular processes leading to the activation of lipogenesis machinery for lipid production (Fig. 1). This discovery has major implications for developing treatments for human diseases such as cancers and metabolic syndromes, as dysregulated metabolism is a hallmark of these diseases.In eukaryotic cells, lipid synthesis is mainly regulated by sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that contain SREBP-1a,-1c and-2. 2, 3 After synthesis, SREBP precursors (w125 kD) bind to the endoplasmic reticulum (ER) membrane in a complex with SREBP cleavage-activating protein (SCAP) and insulininduced gene protein (Insig), which includes Insig-1 and-2 (ER-resident proteins). Lipids are essential components of cellular membranes, while excessive lipids, such as fatty acids and cholesterol, causes toxicity for cells. Therefore, SREBP transcriptional activity and lipid production rates are tightly controlled. SREBPs first need to exit the ER and translocate to the Golgi apparatus for a sequential cleavage by two proteases (site-1 protease (S1P) and site-2 proteases (S2P)), which release the active N-terminal SREBP forms (w65 kD) that enter into the nucleus to activate lipogenic gene expression. 2, 3 The key step controlling SREBPs’ exit from the ER is regulated by SCAP, which binds to COPII-coated vesicles to transport SREBPs from the ER to the Golgi. However, this step is restricted by the ER-resident protein Insig, which directly binds to SCAP to prevent it from interacting with COPII proteins, thereby spatially restricting the SCAP/SREBP complex to the ER. 2 Thus, the key step for SREBP activation is SCAP escaping from Insig binding. Prior to 2015, understanding of SCAP/
DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
影响因子：
7.3
作者：
Guo D;Prins RM;Dang J;Kuga D;Iwanami A;Soto H;Lin KY;Huang TT;Akhavan D;Hock MB;Zhu S;Kofman AA;Bensinger SJ;Yong WH;Vinters HV;Horvath S;Watson AD;Kuhn JG;Robins HI;Mehta MP;Wen PY;DeAngelis LM;Prados MD;Mellinghoff IK;Cloughesy TF;Mischel PS
通讯作者：
Mischel PS
影响因子：
20.8
作者：
Cheng, Chunming;Geng, Feng;Li, Zoe;Zhong, Yaogang;Wang, Huabao;Cheng, Xiang;Zhao, Yue;Mo, Xiaokui;Horbinski, Craig;Duan, Wenrui;Chakravarti, Arnab;Cheng, Xiaolin;Guo, Deliang
通讯作者：
Guo, Deliang