GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism
GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism
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GGPP 消耗通过使 CYB5R3 依赖性类二十烷酸代谢失衡而引发代谢炎症
DOI：
10.1074/jbc.ra120.015020
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Zhang Xue-Na
中科院分区：
文献类型：
--
作者：
Wei Li-Sha;Zheng Yan-Yan;Sun Jie;Wang Pei;Tao Tao;Li Ye-Qiong;Chen Xin;Sang Yong-Juan;Chong Dan-Yang;Zhao Wei;Zhou Yu-Wei;Wang Ye;Jiang Zhi-Hui;Qiu Tian-Tian;Li Chao-Jun;Zhu Min-Sheng;Zhang Xue-Na
后炎症是代谢紊乱的主要炎症并发症，其特征在于许多炎性细胞因子、脂肪因子和脂质介质的产生改变。尽管已经确定了多种炎症网络，但引发炎症的机制长期以来一直存在争议。由于甲羟戊酸途径（MVA）产生丰富的生物活性类异戊二烯，并且异常MVA与炎症/免疫具有表型相关性，我们推测来自MVA的类异戊二烯可能提供了炎症和代谢紊乱之间的因果关系。使用MVA类异戊二烯生产者香叶基香叶基二磷酸合酶（GGPPS）删除的线，我们发现，香叶基香叶基焦磷酸（GGPP）消耗引起明显的metaflammation的脂肪酸，类花生酸中间体，和促炎细胞因子的异常积累证明。我们还发现GGPP异戊烯化细胞色素b5还原酶3（CYB 5 R3）和异戊烯化CYB 5 R3然后从线粒体易位到内质网（ER）池。由于CYB 5 R3是ER中类花生酸代谢所必需的关键NADH依赖性还原酶，因此我们认为GDPP介导的CYB 5 R3异戊二烯化是代谢所必需的。此外，我们观察到辛伐他汀对MVA途径的药理学抑制足以抑制CYB 5 R3易位并诱导平滑肌死亡。因此，我们得出结论，MVA中间体的失调是一个重要的机制，metaflammation启动，其中不平衡的生产类花生酸中间体在ER作为一个重要的致病因素。此外，MVA和类花生酸代谢的相互作用，我们在这里报告说明了代谢途径之间的协调调节模型。
Metaflammation is a primary inflammatory complication of metabolic disorders characterized by altered production of many inflammatory cytokines, adipokines, and lipid mediators. Whereas multiple inflammation networks have been identified, the mechanisms by which metaflammation is initiated have long been controversial. As the mevalonate pathway (MVA) produces abundant bioactive isoprenoids and abnormal MVA has a phenotypic association with inflammation/immunity, we speculate that isoprenoids from the MVA may provide a causal link between metaflammation and metabolic disorders. Using a line with the MVA isoprenoid producer geranylgeranyl diphosphate synthase (GGPPS) deleted, we find that geranylgeranyl pyrophosphate (GGPP) depletion causes an apparent metaflammation as evidenced by abnormal accumulation of fatty acids, eicosanoid intermediates, and proinflammatory cytokines. We also find that GGPP prenylate cytochrome b5 reductase 3 (CYB5R3) and the prenylated CYB5R3 then translocate from the mitochondrial to the endoplasmic reticulum (ER) pool. As CYB5R3 is a critical NADH-dependent reductase necessary for eicosanoid metabolism in ER, we thus suggest that GGPP-mediated CYB5R3 prenylation is necessary for metabolism. In addition, we observe that pharmacological inhibition of the MVA pathway by simvastatin is sufficient to inhibit CYB5R3 translocation and induces smooth muscle death. Therefore, we conclude that the dysregulation of MVA intermediates is an essential mechanism for metaflammation initiation, in which the imbalanced production of eicosanoid intermediates in the ER serve as an important pathogenic factor. Moreover, the interplay of MVA and eicosanoid metabolism as we reported here illustrates a model for the coordinating regulation among metabolite pathways.
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DOI：
10.1016/s1054-8807(03)00104-2
发表时间：
2004
期刊：
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology
影响因子：
--
作者：
Ryu Takata;Shinya Fukasawa;T. Hara;H. Nakajima;A. Yamashina;N. Yanase;J. Mizuguchi
通讯作者：
Ryu Takata;Shinya Fukasawa;T. Hara;H. Nakajima;A. Yamashina;N. Yanase;J. Mizuguchi
影响因子：
64.8
作者：
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影响因子：
13.6
作者：
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通讯作者：
D. Tocher;M. Leaver;P. Hodgson
GGPPS介导的Rab27A香叶基香叶基化通过影响胰岛素颗粒对接池的形成来调节2型糖尿病发展过程中的β细胞功能障碍
影响因子：
7.3
作者：
Jiang, Shan;Shen, Di;Li, Chao-Jun
通讯作者：
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DOI：
10.1111/j.1524-6175.2002.00499.x
发表时间：
2002-07-01
期刊：
Journal of clinical hypertension (Greenwich, Conn.)
影响因子：
--
作者：
Borghi, Claudio;Dormi, Ada;Ambrosioni, Ettore
通讯作者：
Ambrosioni, Ettore