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Publication
HIF2a Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response
Independent of Insulin Signaling.
Authors Ramakrishnan SK, Zhang H, Takahashi S, Centofanti B, Periyasamy S, Weisz K, Chen
Z, Uhler MD, Rui L, Gonzalez FJ, Shah YM
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Cell Metabolism
Year 2016
Date Published 3/1/2016
Volume : Pages 23 : 505 - 16
PubMed Reference 26853750
Abstract Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels
during fasting. The mechanism that attenuates glucagon action following
refeeding is not understood. The present study demonstrates an increase in
perivenous liver hypoxia immediately after feeding, which stabilizes
hypoxia-inducible factor 2a (HIF2a) in liver. The transient postprandial
increase in hepatic HIF2a attenuates glucagon signaling. Hepatocyte-specific
disruption of HIF2a increases postprandial blood glucose and potentiates the
glucagon response. Independent of insulin/AKT signaling, activation of hepatic
HIF2a resulted in lower blood glucose, improved glucose tolerance, and decreased
gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2a
abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a
MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2a ameliorated
hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant
animal models. This study reveals that HIF2a is essential for the acute
postprandial regulation of hepatic glucagon signaling and suggests HIF2a as a
potential therapeutic target in the treatment of diabetes.




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