Quinolinate inhibition of gluconeogenesis is dependent on cytosolic oxalacetate concentration

Abstract

In isolated rat hepatocytes, the phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, quinolinate decreased gluconeogenesis from lactate more than from pyruvate (78 vs 44%). Quinolinate inhibition of PEPCK has been reported to be competitive with oxalacetate (OAA), and therefore higher cytosolic OAA concentrations could be expected to alleviate quinolinate inhibition of PEPCK and hence reduce its effect on gluconeogenesis. With pyruvate as a carbon source, the cytosolic concentration of OAA was higher than with lactate (40 vs 9.7 PM). The levels of OAA were manipulated metabolically by adding asparagine (which provides more cytosolic OAA through the urea cycle) or oleate (which increases malate efllux from the mitochondria). In each of the 8 conditions studied, quinolinate inhibition of gluconeogenesis was inversely related to the levels of OAA in the cytosol. Quinolinate inhibition of asparagine gluconeogenesis was not due to a non-specific effect on urea synthesis. Gluconeogenesis Rat hepatocyte Quinolinate Phosphoenolpyruvate carboxykinase AsparagineOxalocetate