Zonation of hepatic metabolism The fed to fasting transition differentially affects PEPCK protein expression in pericentral and periportal murine hepatocytes

Hepatic glucose metabolism is zonated. Glycolysis is mainly localized in hepatocytes surrounding the hepatic vein (pericentral zone) whereas gluconeogenesis is mainly carried out by hepatocytes surrounding the portal vein (periportal zone). Expression of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK, PCK1) is reduced upon feeding. PEPCK is considered a periportal enzyme but the effects of feeding-fasting transition on PEPCK zonation are unknown. In the present study, laserdissection microscopy, immunohistochemistry and primary periportal and pericentral hepatocytes were used to asses the effects of the feeding-fasting transition on zonation of PEPCK gene and protein. PEPCK protein expression was reduced in pericentral but not in periportal hepatocytes in fed versus fasted mice. In alloxan-induced type 1 diabetic mice, which lack insulin, Pepck mRNA expression and protein levels did not increase upon fasting. Nevertheless, PEPCK was still zonated along the liver acinus suggesting. In conclusion, our data show that the effects of the feeding to fasting response on PEPCK protein expression are likely mediated by insulin and mostly affects pericentral hepatocytes. Nevertheless, additonal, yet to be determined factors regulate zonation of PEPCK.