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

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. [Display omitted] • Increases in hepatic cytosolic NADH/NAD⁺ (reductive stress) change the hepatic transcriptome • These transcriptional changes are mediated by ChREBP, which is activated by reductive stress • GCKR ' s metabolic pleiotropy is explained in part by ChREBP's activation via reductive stress • Multiple human metabolic traits may be influenced by a GCKR -NADH/NAD⁺-ChREBP-FGF21 axis Singh et al. find that increased hepatic cytosolic NADH/NAD⁺ activates the transcription factor ChREBP. This pathway underlies some metabolic traits associated with common GCKR genetic variants, such as circulating FGF21 and triglyceride levels, and likely more generally influences certain deleterious metabolic traits in humans. [ABSTRACT FROM AUTHOR]