Abstract EN:

In the liver, the regulation of glycolytic and lipogenic gènes like L-pyruvate kinase (L-PK), acetyl-CoA carboxilase (ACC) and fatty acid synthase (FAS), which catalyze fatty acid synthesis from glucose, requires both high glucose and insulin concentration. Recently, the transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein) has emergea has a major mediator of glucose action on L-PK gene expression. However, in the beginning of this work, its role in the regulation of lipogenic gene was unknown. In this context, we clearly show that decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous L-PK, FAS, and ACC gene expression, thereby demonstrating the direct implication of ChREBP in glucose action in liver. The present study also reveals that ChREBP gene expression as well as ChREBP nuclear protein content are significantly increased in liver of ob/ob mice, and that liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by decreasing lipogenic rates. As consequence, overall glucose tolerance and insulin sensitivity were restored in ob/ob mice. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice. Finally, we demonstrate that polyunsaturated fatty acid, by preventing ChREBP gene expression and ChREBP nuclear translocation, decrease glycolytic and lipogenic gene expression and could prevent the development of the hepatic steatosis observed in the pathology of obesity and insulin resistance.