EVIDENCE FROM TRANSGENIC MICE THAT MYC REGULATES HEPATIC GLYCOLYSIS

The product of the c-myc proto-oncogene (c-Myc) is involved in the con trol of cell proliferation, differentiation, and apoptosis. It acts as a transcription factor that recognizes the CACGTG motif. This sequenc e has also been found in the glucose-responsive elements of genes invo lved in the control of liver glycolysis and lipogenesis. To determine whether c-Myc can regulate hepatic carbohydrate metabolism in vivo, tr ansgenic mice that overexpress c-myc under control of the P-enolpyruva te carboxykinase (PEPCK) gene promoter have been generated. These mice showed a threefold increase in c-Myc protein in liver nuclei. Hepatoc ytes from transgenic mice were normal and did not acquire the fetal ph enotype. 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 incr ease in liver lactate content and a fivefold induction of lactate prod uction by hepatocytes in primary culture. The expression of the 6-phos phofructo-2-kinase gene was also increased in the liver of these trans genic mice. The induction of hepatic glycolysis was related with an in crease in the expression (about fourfold) and activity (about threefol d) 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. Th e 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 meta bolism led to a marked reduction of blood glucose (25%) and insulin (4 0%) concentrations in starvation, whereas the fall in bath was only 10 % in fed mice. Thus, liver glucose metabolism could determine tile blo od glucose and insulin set points in the transgenic mice. All these re sults indicated that the increase in c-Myc protein was able to induce liver glucose utilization and accumulation, and suggested that c-Myc t ranscription factor is involved in the control in vivo of liver carboh ydrate metabolism.