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ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.

Abstract
Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
AuthorsCharandeep Singh, Byungchang Jin, Nirajan Shrestha, Andrew L Markhard, Apekshya Panda, Sarah E Calvo, Amy Deik, Xingxiu Pan, Austin L Zuckerman, Amel Ben Saad, Kathleen E Corey, Julia Sjoquist, Stephanie Osganian, Roya AminiTabrizi, Eugene P Rhee, Hardik Shah, Olga Goldberger, Alan C Mullen, Valentin Cracan, Clary B Clish, Vamsi K Mootha, Russell P Goodman
JournalCell metabolism (Cell Metab) Vol. 36 Issue 1 Pg. 144-158.e7 (01 02 2024) ISSN: 1932-7420 [Electronic] United States
PMID38101397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2023 Elsevier Inc. All rights reserved.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Glucokinase
  • Glucose
  • Transcription Factors
  • MLXIPL protein, human
Topics
  • Humans
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Genome-Wide Association Study
  • Glucokinase (genetics, metabolism)
  • Glucose (metabolism)
  • Liver (metabolism)
  • Transcription Factors (metabolism)

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