Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate

Abstract

Transport and metabolism of dicarboxylates may be important in the glial-neuronal metabolic interplay. Further, exogenous dicarboxylates have been suggested as cerebral energy substrates. After intrastriatal injection of [14C]fumarate or [14C]malate, glutamine attained a specific activity 4.1 and 2.6 times higher than that of glutamate, respectively, indicating predominantly glial uptake of these four-carbon dicarboxylates. In contrast, the three-carbon dicarboxylate [14C]malonate gave a specific activity in glutamate which was approximately five times higher than that of glutamine, indicating neuronal uptake of malonate. Therefore, neurones and glia take up different types of dicarboxylates, probably by different transport mechanisms. Labelling of alanine from [14C]fumarate and [14C]malate demonstrated extensive malate decarboxylation, presumably in glia. Intravenous injection of 75 μmol [U-13C]fumarate rapidly led to high concentrations of [U-13C]fumarate and [U-13C] malate in serum, but neither substrate labelled cerebral metabolites as determined by 13C NMR spectroscopy. Only after conversion of [U-13C]fumarate into serum glucose was there 13C-labelling of cerebral metabolites, and only at <10% of that obtained with 75 μmol [3-13C] lactate or [2-13C]acetate. These findings suggest a very low transport capacity for four-carbon dicarboxylates across the blood-brain barrier and rule out a role for exogenous fumarate as a cerebral energy substrate.