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Lipid restriction in Familial Hypolipidemia 2 amplifies type I interferon response and suppresses IL-1beta production in a prenylation-dependent fashion

ABSTRACT: Familial Combined Hypolipidemia (FHBL2) is a genetic disorder caused by loss-of-function mutations in the Angiopoietin-like 3 (ANGPTL3) gene. FHBL2 subjects exhibit hypolipidemia and protection from cardiometabolic diseases. Here, we explored the hypothesis that immunometabolic events contribute to this phenotype. In FHBL2 subjects, circulating leukocytes exhibited lower content of intracellular lipids, together with a spontaneous type I IFN signature. Higher sensitivity to IFN stimulation was observed in FHBL2 monocytes ex vivo, as well as and in healthy monocytes deprived of lipids in vitro. Lipid restriction reduced mitochondrial metabolism and activated the mevalonate and isoprenoid synthetic pathway. Of note, a prenylation inhibitor reverted the high IFN response in lipid-deprived monocytes. Lipid restriction equaled IFN in repressing, in a prenylation-dependent fashion, the production of the inflammatory and proatherogenic cytokine IL-1. In summary, we uncovered a novel immunometabolic mechanism linking lipid deprivation in monocytes, isoprenoid synthesis, enhanced IFN response, and IL-1 control. This circuit may provide an immunometabolic basis for the protection from atherosclerotic diseases in hypolipidemic subjects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307462 | GEO | 2025/11/28

REPOSITORIES: GEO

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Project description:Prenylation consists of the modification of proteins with either farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP) at a cysteine near the C-terminus of target proteins to generate thioether-linked lipidated proteins. Given the widespread involvement of prenylation in protein localization, membrane trafficking, and cellular signaling, dysregulation of prenylation and prenylated proteins have been implicated in the pathogenesis of numerous diseases. In recent work, metabolic labeling with alkyne-containing isoprenoid analogues including C15AlkOPP has been used to identify prenylated proteins and track their levels in different diseases. Here, a systematic study of the impact of isoprenoid length on proteins labeled with these probes was performed. First docking experiments were used to examine how lipid length might impact prenyltransferase selectivity. Next, chemical synthesis was used to generate two new analogues, C15hAlkOPP and C20AlkOPP, bringing the total number of compounds to four used in this study. Enzyme kinetics were used to evaluate these molecules as substrates for prenyltransferases in vitro. In cellulo metabolic labeling, enrichment and proteomic analysis were performed, resulting in the labeling of 8 proteins for C10AlkOPP (lipid length = 12 atoms), 70 proteins for C15AlkOPP (lipid length = 16 atoms), 41 proteins for C15hAlkOPP (lipid length = 17 atoms) and 7 proteins for C20AlkOPP (lipid length = 20 atoms). While C10AlkOPP was the most selective for farnesylated proteins and C20AlkOPP was most selective for geranylgeranylated proteins, the number of proteins identified using those probes was relatively small. In contrast, C15AlkOPP labeled the most proteins including representatives from all classes of prenylated proteins. Functional analysis of these analogues demonstrated that C15AlkOPP was particularly well suited for biological studies since it was efficiently incorporated in cellulo, was able to confer correct plasma membrane localization of H-Ras protein and complement the effects of GGPP depletion in macrophages to yield correct cell polarization and filopodia. Collectively, these results indicate that C15AlkOPP is a biologically functional, universal probe for metabolic labeling experiments that has minimal effects on cellular physiology.

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Lipid restriction in Familial Hypolipidemia 2 amplifies type I interferon response and suppresses IL-1beta production in a prenylation-dependent fashion

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