Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets

Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure

“…While transcriptional regulation and localization of the two splice isoforms, as demonstrated in this study seem to be of high importance for the regulation of ChREBP and activity, there are additional mechanisms that have been previously shown to tightly regulate ChREBP location and activity. ChREBP is regulated by carbohydrate metabolites and other metabolic signals 19 , 38 , including Ca ++ flux, which dissociates its binding to sorcin allowing nuclear translocation in beta cells 18 , and several posttranslational modifications [reviewed in 39 ], which may affect its stability and the binding of co-factors and co-activators 40 , 41 . Additionally, nuclear retention of ChREBP’s mRNA 42 , and sequestration of ChREBP’s heterodimer partner, Mlx, in lipid droplets play important roles in regulating ChREBP activity 43 .…”

Nonsynonymous single-nucleotide polymorphisms in the G6PC2 gene affect protein expression, enzyme activity, and fasting blood glucose

“…We previously showed that luciferase activity is induced by elevated glucose in this assay but repressed by cotransfection with a plasmid encoding G6PC1 ( 22 ). We hypothesized that G6PC1 reduces intracellular G6P, the key metabolite in glucose-regulated gene transcription ( 22 , 29 ). Again, taking advantage of the high G6PC2 protein expression conferred by the pJPA5 vector, this assay was used to study G6PC2 activity in intact cells.…”

Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae

“…For example, glucose-6-phosphate is a substrate for the PPP, which supplies NADPH for lipogenesis [ 82 ]. This sugar phosphate activates ChREBP [ 11 , 107 ]. Dihydroxyacetone phosphate activates MTORC-1, which activates SREBP-1c [ 108 ].…”