Lipid restriction in Familial Hypolipidemia 2 amplifies type I interferon response and suppresses IL-1beta production in a prenylation-dependent fashion
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. Overall design: Comparative gene expression profiling analysis of RNA-seq data for PBMC of FHBL2 Homozygous patients (Angptl3 p.s17*/p.s17*) and control patients