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.

中文翻译：

---

GGPP 消耗通过使 CYB5R3 依赖的类二十烷酸代谢失衡而引发元炎症。

Metaflammation 是代谢紊乱的主要炎症并发症，其特征是许多炎性细胞因子、脂肪因子和脂质介质的产生发生改变。虽然已经确定了多个炎症网络，但引发元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，而异常 MVA 与炎症/免疫表型相关，我们推测来自 MVA 的类异戊二烯可能提供了异戊二烯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) 缺失的谱系，我们发现香叶基香叶基焦磷酸 (GGPP) 消耗会导致明显的异火，如脂肪酸、类花生酸中间体、和促炎细胞因子。我们还发现 GGPP 异戊二烯化细胞色素 b5 还原酶 3 (CYB5R3) 和异戊二烯化 CYB5R3 然后从线粒体易位到内质网 (ER) 池。由于 CYB5R3 是 ER 中类花生酸代谢所必需的关键 NADH 依赖性还原酶，因此我们建议 GGPP 介导的 CYB5R3 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 CYB5R3 易位并诱导平滑肌死亡。因此，我们得出结论，MVA 中间体的失调是发生变炎的重要机制，其中内质网中类二十烷酸中间体的不平衡产生是一个重要的致病因素。而且，