Transcriptional Control of Metabolic Regulation Genes by Carbohydrates

Glucose can modulate the transcription of many genes, particularly those encoding enzymes of liver metabolism. The transcriptional effect of glucose can be indirect, being mediated in vivo by hormonal variations, especially increase in insulin and decrease in glucagon secretion. Whereas the transcription of the glucokinase gene, for example, is stimulated by insulin without the aid of glucose, the transcriptional activation of most glycolytic and lipogenic genes in hepatocytes requires the presence of both glucose and insulin. The role of insulin in the activation of these genes seems mainly to stimulate glucokinase synthesis, and thus to permit glucose phosphorylation. In some cells in which hexokinase activity is constitutive, the glucose-dependent activation of the same genes does not require insulin and, in addition, can be produced by the nonmetabolisable analog, 2-deoxyglucose. In hepatocytes, the insulin effect on the glucose-dependent activation of the L-pyruvate kinase gene can be reproduced by fructose at low concentrations. Fructose probably acts through the fructose 1-phosphate dependent deinhibition of glucokinase activity. A glucose/carbohydrate element has been identified on the L-type pyruvate kinase and spot 14 gene promoters. It is able to bind, in vitro, transcriptional factors of the MLTF/USF family and could act in cooperation with tissue-specific contiguous elements, such as the HNF4 binding site in the L-type pyruvate kinase gene.