Hepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity.

TitleHepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity.
Publication TypeJournal Article
Year of PublicationForthcoming
AuthorsDuangjan, C, Arpawong, TEm, Spatola, BN, Curran, SP
JournalGeroscience
ISSN Number2509-2723
KeywordsHepatocytesm, Insulin homeostasis, Insulin-degrading enzyme (IDE), Liver, NRF2, Proteostasis, WDR23
Abstract

Maintaining insulin homeostasis is critical for cellular and organismal metabolism. 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 a new molecular determinant of metabolic health in humans.

DOI10.1007/s11357-024-01196-y
Citation Key13990
PubMed ID38767782
PubMed Central ID6028526
Grant ListAG063947 / AG / NIA NIH HHS / United States
AG058610 / AG / NIA NIH HHS / United States
AG068345 / AG / NIA NIH HHS / United States