Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin-degrading enzyme activity

Abstract

SUMMARYClearance of circulating insulin is critical for metabolic homeostasis. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here we establish a hepatic regulatory axis for IDE through WDR23-proteostasis.Wdr23KOmice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lackingWDR23also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, and mTOR. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE whenWDR23is ablated. Moreover, an analysis of human genetic variation inWDR23across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association ofWDR23with altered hemoglobin A1C (HbA1c) levels in older adults that supports the use of WDR23 as new molecular determinant of metabolic health in humans.