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

Carbohydrates mediate their conversion to triglycerides in the liver by pro moting both rapid posttranslational activation of rate-limiting glycolytic and lipogenic enzymes and transcriptional induction of the genes encoding m any of these same enzymes. The mechanism by which elevated carbohydrate lev els 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 p rotein (ChREBP} in rat fivers is specifically induced by a high carbohydrat e diet. ChREBP's DNA-binding specificity in vitro precisely correlates with promoter activity in vivo. Furthermore, forced ChREBP overexpression in pr imary hepatocytes activates transcription from the L-type Pyruvate kinase p romoter in response to high glucose levels. The DNA-binding activity of ChR EBP can be modulated in vitro by means of changes in its phosphorylation st ate, 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 a nd storage characteristic of obesity.