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  2. Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization

Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization

  • Proc Natl Acad Sci U S A. 2022 Feb 8;119(6):e2111737119. doi: 10.1073/pnas.2111737119.
Cheng Chen 1 Lijie Gu 1 David J Matye 1 2 Yung-Dai Clayton 1 Mohammad Nazmul Hasan 1 Yifeng Wang 2 Jacob E Friedman 1 Tiangang Li 3 2
Affiliations

Affiliations

  • 1 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
  • 2 Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160.
  • 3 Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; tiangang-li@ouhsc.edu.
Abstract

Hepatic Insulin resistance is a hallmark feature of nonalcoholic fatty liver disease and type-2 diabetes and significantly contributes to systemic Insulin resistance. Abnormal activation of nutrient and stress-sensing kinases leads to serine/threonine phosphorylation of Insulin Receptor substrate (IRS) and subsequent IRS Proteasome degradation, which is a key underlying cause of hepatic Insulin resistance. Recently, members of the cullin-RING E3 Ligases (CRLs) have emerged as mediators of IRS protein turnover, but the pathophysiological roles and therapeutic implications of this cellular signaling regulation is largely unknown. CRLs are activated upon cullin neddylation, a process of covalent conjugation of a ubiquitin-like protein called Nedd8 to a cullin scaffold. Here, we report that pharmacological inhibition of cullin neddylation by MLN4924 (Pevonedistat) rapidly decreases hepatic glucose production and attenuates hyperglycemia in mice. Mechanistically, neddylation inhibition delays CRL-mediated IRS protein turnover to prolong Insulin action in hepatocytes. In vitro knockdown of either cullin 1 or cullin 3, but not other cullin members, attenuates insulin-induced IRS protein degradation and enhances cellular Insulin signaling activation. In contrast, in vivo knockdown of liver cullin 3, but not cullin 1, stabilizes hepatic IRS and decreases blood glucose, which recapitulates the effect of MLN4924 treatment. In summary, these findings suggest that pharmacological inhibition of cullin neddylation represents a therapeutic approach for improving hepatic Insulin signaling and lowering blood glucose.

Keywords

MLN4924; cullin; diabetes; fatty liver; insulin resistance.

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