A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver

TLDR

Carbohydrates promote triglyceride synthesis in the liver by activating key glycolytic and lipogenic enzymes and inducing transcription of related genes, yet the transcriptional mechanism remains unclear. The study aims to identify and purify a transcription factor that binds the carbohydrate response element in the L‑type pyruvate kinase promoter. The authors purified and characterized this ChRE‑binding protein (ChREBP) from rat liver. ChREBP is activated by high carbohydrate intake, its DNA‑binding correlates with LPK promoter activity, can be modulated by phosphorylation, and its overexpression drives glucose‑responsive transcription, indicating a central role in long‑term carbohydrate storage and obesity.

Abstract

Carbohydrates mediate their conversion to triglycerides in the liver by promoting both rapid posttranslational activation of rate-limiting glycolytic and lipogenic enzymes and transcriptional induction of the genes encoding many of these same enzymes. The mechanism by which elevated carbohydrate levels affect transcription of these genes remains unknown. Here we report the purification and identification of a transcription factor that recognizes the carbohydrate response element (ChRE) within the promoter of the L-type pyruvate kinase (LPK) gene. The DNA-binding activity of this ChRE-binding protein (ChREBP) in rat livers is specifically induced by a high carbohydrate diet. ChREBP's DNA-binding specificity in vitro precisely correlates with promoter activity in vivo . Furthermore, forced ChREBP overexpression in primary hepatocytes activates transcription from the L-type Pyruvate kinase promoter in response to high glucose levels. The DNA-binding activity of ChREBP can be modulated in vitro by means of changes in its phosphorylation state, suggesting a possible mode of glucose-responsive regulation. ChREBP is likely critical for the optimal long-term storage of excess carbohydrates as fats, and may contribute to the imbalance between nutrient utilization and storage characteristic of obesity.