GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism

Metaflammation is a primary inflammatory complication of metabolic disorders characterized by altered production of many inflammatory cytokines, adipokines and lipid mediators. While multiple inflammation networks have been identified, the mechanisms by which metaflammation is initiated have long been controversial. As 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 isoprenoids producer geranygeranyldiphosphate synthase (GGPPS) deleted, we find that 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 ER pool. As CYB5R3 is a critical NADH-dependent reductase necessary for eicosanoids metabolism in ER, we thus suggests that GGPP-mediated CYB5R3 prenylation is necessary for eicosanoid metabolism. In addition, we observe that pharmacological inhibition of 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 ER serve as an important pathogenic factor. Moreover, the interplay of MVA and eicosanoids metabolism as we reported here illustrates a model for the coordinating regulation among metabolite pathways.