A fly GWAS for purine metabolites identifies human FAM214 homolog medusa, which acts in a conserved manner to enhance hyperuricemia-driven pathologies by modulating purine metabolism and the inflammatory response

Abstract

model of hyperuricemia and uric acid crystallization ("concretion formation") in the kidney-like Malpighian tubule. Medusa (mda) activity increased urate levels and inflammatory response programming. Conversely, whole-body mda knockdown decreased purine synthesis precursor phosphoribosyl pyrophosphate, uric acid, and guanosine levels; limited formation of aggregated uric acid concretions; and was sufficient to rescue lifespan reduction in the fly hyperuricemia and gout model. Levels of mda homolog FAM214A were elevated in inflammatory M1-and reduced in anti-inflammatory M2-differentiated mouse bone marrow macrophages, and influenced intracellular uric acid levels in human HepG2 transformed hepatocytes. In conclusion,

The dysregulation of immune cells induced by uric acid: mechanisms of inflammation associated with hyperuricemia and its complications

“…M1/M2 populace dysregulation is evident in HUA and its associated complications ( 35 , 68 ). Changes to the macrophage population could significantly affect UA concentrations, subsequently amplifying HUA complications.…”

“…M1/M2 populace dysregulation is evident in HUA and its associated complications (35,68). Changes to the macrophage (69).…”