Charandeep 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
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...
January 2, 2024: Cell Metabolism