RT Journal Article
SR Electronic
T1 Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin-degrading enzyme activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.24.516014
DO 10.1101/2022.11.24.516014
A1 Chatrawee Duangjan
A1 Thalida Em Arpawong
A1 Brett N. Spatola
A1 Sean P. Curran
YR 2022
UL http://biorxiv.org/content/early/2022/11/25/2022.11.24.516014.abstract
AB Clearance 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. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also 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 when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults that supports the use of WDR23 as new molecular determinant of metabolic health in humans.Competing Interest StatementThe authors have declared no competing interest.