Dagdeviren S, Hoang MF, Sarikhani M, Meier V, Benoit JC, Okawa MC, Melnik VY, Ricci-Blair EM, Foot N, Friedline RH, Hu X, Tauer LA, Srinivasan A, Prigozhin MB, Shenoy SK, Kumar S, Kim JK, Lee RT. 2023. An insulin-regulated arrestin domain protein controls hepatic glucagon action. The Journal of biological chemistry. 299(8):105045. Pubmed: 37451484 DOI:10.1016/j.jbc.2023.105045


Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the arrestin domain-containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here, we show that mice with a global deletion of the ARRDC4 protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 coimmunoprecipitates with the glucagon receptor, and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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Rich Lee seeks to understand heart failure and metabolic diseases that accompany human aging, and translate that understanding into therapies. Lee is an active clinician, regularly treating patients at Brigham and Women’s Hospital.

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