Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.24.516014v1?rss=1

Authors: Duangjan, C., Arpawong, T. E., Spatola, B. N., Curran, S. P.

Abstract:
The clearance of insulin from circulation is critical for metabolic homeostasis. Insulin is depleted in the liver by the insulin degrading enzyme (IDE). WDR23 is a substrate receptor of the Cul4-ubiquitin ligase complex and acts as a sophisticated regulator of protein activation and turnover. Here we establish hepatic WDR23 in the regulation of insulin metabolism by regulating IDE. An unbiased proteomic analysis of liver tissue of mice lacking Wdr23 revealed a significant increase in the steady state levels of IDE which accompanied reduced circulating insulin and diminished sensitivity to insulin stimulation. A comparative assessment of the transcriptomic changes in livers from animals with and without WDR23 reveals significant changes in the targets responding to insulin and glucose receptor signaling. Furthermore, phosphorylation of the insulin signaling cascade proteins, IRS-1, AKT, MAPK and mTOR were dysregulated in Wdr23KO mice. These findings are recapitulated in cultured human cell models with genetic ablation of Wdr23 revealing a conserved role for WDR23 from mice to humans. 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.

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