The product of the c-myc proto-oncogene (c-Myc) is involved in the control of 
cell proliferation, differentiation, and apoptosis. It acts as a transcription 
factor that recognizes the CACGTG motif. This sequence has also been found in 
the glucose-responsive elements of genes involved in the control of liver 
glycolysis and lipogenesis. To determine whether c-Myc can regulate hepatic 
carbohydrate metabolism in vivo, transgenic mice that overexpress c-myc under 
control of the P-enolpyruvate carboxykinase (PEPCK) gene promoter have been 
generated. These mice showed a threefold increase in c-Myc protein in liver 
nuclei. Hepatocytes from transgenic mice were normal and did not acquire the 
fetal phenotype. However, transgenic mice showed higher levels (threefold) of 
L-type pyruvate kinase mRNA and enzyme activity than control mice. The increase 
in pyruvate kinase activity led to a three- to fivefold increase in liver 
lactate content and a fivefold induction of lactate production by hepatocytes in 
primary culture. The expression of the 6-phosphofructo-2-kinase gene was also 
increased in the liver of these transgenic mice. The induction of hepatic 
glycolysis was related with an increase in the expression (about fourfold) and 
activity (about threefold) of liver glucokinase, whereas no change was noted in 
hexokinase-I. This change in glucokinase activity led to an increase in both 
glucose 6-phosphate and glycogen contents in the liver of transgenic mice. The 
expression of the liver-specific glucose transporter GLUT2 was also increased in 
transgenic mice, whereas no change was noted in the mRNA concentration of GLUT1. 
Furthermore, the changes of liver glucose metabolism led to a marked reduction 
of blood glucose (25%) and insulin (40%) concentrations in starvation, whereas 
the fall in both was only 10% in fed mice. Thus, liver glucose metabolism could 
determine the blood glucose and insulin set points in the transgenic mice. All 
these results indicated that the increase in c-Myc protein was able to induce 
liver glucose utilization and accumulation, and suggested that c-Myc 
transcription factor is involved in the control in vivo of liver carbohydrate 
metabolism.