Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin-degrading enzyme
Year: 2022
Type: preprint
Abstract: ABSTRACT 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, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. 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, supporting the use of WDR23 as new molecular determinant of metabolic health in humans.
Institution: University of Southern California
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1180809207, G2203052344, G2411201074, G3102428995, Characterizing WDR23 in Alzheimer's disease pathology, Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis, G680966822, The University of Southern California and Buck Institute Nathan Shock Center, Health and Retirement Study: Yrs 35-40, G920585386
OpenAlex ID: W4310202191