GGPP depletion initiates metaflammation through disequilibrating CYB5R3-dependent eicosanoid metabolism

Abstract

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.

CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis of lung cancer cells via PERK-ATF4 and IRE1α-JNK pathway

“…CYB5R2 localizes in the Golgi apparatus and nucleoplasm and is highly expressed in the testis. In CYB5R3-overexpressing H1299 cells, CYB5R3 was mainly located in the ER and undergoes posttranslational modi cations, leading to changes in subcellular localization [40][41][42] . Recent studies have suggested that prenylated CYB5R3 translocates from the mitochondria to the ER, while non-prenylated CYB5R3 localizes in the mitochondria 41 .…”

“…In CYB5R3-overexpressing H1299 cells, CYB5R3 was mainly located in the ER and undergoes posttranslational modi cations, leading to changes in subcellular localization [40][41][42] . Recent studies have suggested that prenylated CYB5R3 translocates from the mitochondria to the ER, while non-prenylated CYB5R3 localizes in the mitochondria 41 . In particular, geranylgeranyl diphosphate synthase (GGPPS), which is involved in CYB5R3 prenylation, is overexpressed in lung adenocarcinoma 40 .…”

The thymus regulates skeletal muscle regeneration by directly promoting satellite cell expansion

“…q-PCR assay Quantitative RT-PCR was performed, as described previously (56,57). Total RNA was extracted from the tissues using RNAiso Plus (9109, Takara Bio) according to the manufacturer's instructions.…”

Geranylgeranyl pyrophosphate (GGPP) is associated with hepatic lipid accumulation and insulin resistance in MAO by prenylating Perilipin4

“…Isoprenoid geranylgeranyl diphosphate (GGPP) is a crucial intermediator in the mevalonate pathway (MVA) for cholesterol, terpene, and terpenoid synthesis, which mainly occurred in the liver [18,19]. GGPP is involved in protein prenylation, a post-translational modification essential for the functioning of many peripheral and signal transduction proteins containing cysteine residues in the CaaX motif, such as SREBP1 and CYB5R3 [20,21].…”