IN-VIVO AND IN-VITRO REGULATION OF HEPATIC GLUCAGON RECEPTOR MESSENGER-RNA CONCENTRATION BY GLUCOSE-METABOLISM

We have recently cloned the murine glucagon receptor (GR) gene and sho wn that it is expressed mainly in liver, In this organ, the glucagon-G R system is involved in the control of glucose metabolism as it initia tes a cascade of events leading to release of glucose into the blood s tream, which is a main feature in several physiological and pathologic al conditions, To better define the metabolic regulators of Gn express ion in liver we analyzed GR mRNA concentration in physiological condit ions associating various glucose metabolic pathways in vivo and in vit ro in the rat and in the mouse, First, we report that the concentratio n of the GR mRNA progressively increased from the first day of life to the adult stage. This effect was abolished when newborn rodents were fasted, Second, under conditions where intrahepatic glucose metabolism was active such as during fasting, diabetes, and hyperglycemic clamp, the concentration of GR mRNA increased independent of the origin of t he pathway that generated the glucose flux. These effects were blunted when hyperglycemia was corrected by phlorizin treatment of diabetic r ats or not sustained during euglycemic clamp, In accordance with these observations, we demonstrated that the glycolytic substrates glucose, mannose, and fructose, as well as the gluconeognic substrates glycero l and dihydroxyacetone, increased the concentration of GR mRNA in prim ary cultures of hepatocytes from fed rats, Glucagon blunted the effect of glucose without being dominant, The stimulatory effect of those su bstrates was not mimicked by the nonmetabolizable carbohydrate L-gluco se or the glucokinase inhibitor glucosamine or when hepatocytes were i solated from starved rats, In addition, inhibitors of gluconeogenesis and lipolysis could decrease the concentration of GR mRNA from hepatoc ytes of starved rats, Combined, these data strongly suggest that gluco se flux in the glycolytic and gluconeogenic pathways at the level of t riose intermediates could control expression of GR mRNA and participat e in controlling its own metabolism.