Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes

Fibroblast growth factor 21 (FGF21) has beneficial effects of improving the plasma glucose and lipid profiles in diabetic rodents. Here, we investigated carbohydrate response element binding protein (ChREBP) involvement in the regulation of FGF21 mRNA expression in liver. Glucose stimulation and adenoviral overexpression of dominant active ChREBP increased FGF21 mRNA. Consistently, adenoviral expression of dominant negative Mlx inhibited glucose induction of FGF21 mRNA. Furthermore, deletion studies of mouse FGF21 gene promoter (−2000 to +65 bp) revealed a glucose responsive region between −74 and −52 bp. These findings suggest that FGF21 expression is regulated by ChREBP.     

Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice

Mlx and ChREBP form a heterodimer to regulate glucose-mediated gene expression in the liver. This study was performed to determine if the metabolic syndrome might be improved using dominant negative Mlx (dnMlx). An adenovirus bearing dnMlx was constructed and used to test the inhibitory effect of dnMlx on lipogenesis both in vitro and in vivo. Adenoviral overexpression of dnMlx in rat hepatocytes inhibited expression of glucose-regulated genes, including Chrebp and Transketolase, which constitute a positive feedback loop in the regulation of Chrebp gene expression. Adenoviral overexpression of dnMlx in 25-week-old male C57BL/6J mice reduced hepatic triglyceride contents and improved glucose intolerance by inhibiting expression of Glucose-6-phosphatase and Elovl6 mRNA in addition to lipogenic enzymes. In conclusion, overexpression of dnMlx improves glucose intolerance by inhibiting expression not only of lipogenic enzymes but also other important genes such as Glucose-6-phosphatase and Elovl6.