The mechanism by which adenosine decreases gluconeogenesis from lactate in isolated rat hepatocytes

Abstract

Incubation of hepatocytes from 24 h-starved rats in the presence of 0.5 mM-adenosine decreased gluconeogenesis from lactate, but not from alanine. The inhibition of gluconeogenesis was associated with a stimulation of ketone-body production and an inhibition of pyruvate oxidation. These metabolic changes were suppressed in the presence of iodotubercidin (an inhibitor of adenosine kinase), but were reinforced in the presence of deoxycoformycin (an inhibitor of adenosine deaminase); 2-chloroadenosine induced no change in gluconeogenesis from lactate. These data indicate that the inhibition of gluconeogenesis by adenosine probably results from its conversion into adenine nucleotides. In the presence of lactate or pyruvate, but not with alanine or asparagine, this conversion resulted in a decrease in the [ATP]/[ADP] ratio in both mitochondrial and cytosolic compartments. Adenosine decreased the Pi concentration with all gluconeogenic substrates.

Metabolism of adenosine through adenosine kinase inhibits gluconeogenesis in isolated rat hepatocytes

“…However, adenosine increased gluconeogenesis from asparagine but did not affect ketonebody release; it had no effect on gluconeogenesis and ketonebody release with alanine, serine and dihydroxyacetone (Table 1). These results were obtained at 0.5 m M adenosine, which is sufficient to inhibit gluconeogenesis maximally [4]. They showed that (a) the increase in ketogenesis was dependent on the glnconeogenic substrates used, (b) the changes in gluconeogenesis and ketogenesis were not necessarily linked, and (c) the increase in ketone-body release was more pronounced in the presence of pyruvate than in the presence of lactate.…”

“…The inhibition of gluconeogenesis from lactate or pyruvate was also suppressed by the addition of iodotubercidin and enhanced by the addition of deoxycoformycin [4]. Therefore, the inhibitory effect of adenosine on gluconeogenesis was due to its conversion through adenosine kinase.…”

“…In the presence of lactate or pyruvate, adenosine conversion through adenosine kinase decreases the mitochondrial ATP/ADP ratio [4], a regulator of pyruvate carboxylase. Moreover, adenosine mimics the effects of oxalate, an inhibitor of pyruvate carboxylase (see Table 2).…”

“…However, such a mechanism cannot explain the inhibition of gluconeogenesis from other substrates; indeed, pyruvate carboxylase is not involved in gluconeogenesis from asparagine, dihydroxyacetone or glutamine. Moreover, if adenosine modifies the ATP/ADP ratio in the presence of lactate and pyruvate, it is not the case with asparagine and alanine [4]. Therefore, adenosine conversion through adenosine kinase induces other metabolic changes which are responsible for the inhibition of gluconeogenesis.…”

“…Recently, we reported that the inhibition of gluconeogenesis from lactate was associated with an increased ketone-body release [4]. This was unexpected, since inhibition of gluconeogenesis is usually associated with a decrease in ketogenesis both in vivo and in vitro [5-111. On the other hand, there is no information concerning the effect of adenosine on ketone-body release in the presence of the other substrates.…”