Energy cost of gluconeogenesis in rat liver

Abstract

The notion is presented that recycling of carbon between the steps pyruvate to P-enolpyruvate, and fructose diphosphate to fructose-6-P, is involved in the overall control of hepatic gluconeogenesis in both normal and pathological states. This results in a higher than theoretical energy cost for gluconeogenesis, which may be revealed by low apparent P:O ratios when calculated on the basis of the theoretical increment of 6 moles of ATP used per mole of glucose formed, compared with the observed increment of respiration when the rate of gluconeogenesis is altered. The concept is developed that the rate of gluconeogenesis is controlled either directly by changes in the concentration of factors modifying pyruvate carboxylase or indirectly by alterations of the activity of pyruvate kinase. If the activity of the latter enzyme is increased, flux through the loop Pyr → OAA → PEP → Pyr will be increased and net gluconeogenesis decreased. Since the inhibitory effects of alanine and ATP on pyruvate kinase can be overcome by low concentrations of fructose diphosphate, interactions in the segment of the gluconeogenic pathway from P-enolpyruvate to glucose, although not able to affect gluconeogenesis flux directly, can control it indirectly by alterations of the fructose diphosphate concentration. Interactions discussed are variations of the citrate concentration, which will affect the activity of phosphofructokinase, and altered metabolic states caused by changes of the state of reduction of the cytosolic pyridine nucleotides. By taking into account the possibility that high rates of carbon recycling between pyruvate and P-enol-pyruvate occur relative to the net rate of gluconeogenesis, the relationship between changes of the cytosolic pyridine nucleotide oxidation-reduction state and the overall control of gluconeogenesis is clarified.