The citric acid cycle intermediate citrate plays a crucial role in metabolic processes like fatty acid synthesis, glucose metabolism and β-oxidation. Citrate is imported from the circulation across the plasma membrane into liver cells mainly by the sodium-dependent citrate transporter NaCT (SLC13A5). Deletion of NaCT from mice led to metabolic changes similar to caloric restriction and therefore NaCT has been proposed as an attractive therapeutic target for the treatment of obesity and type-2 diabetes. In this study we have expressed mouse and human NaCT into Xenopus oocytes and examined some basic functional properties of those transporters. Interestingly, striking differences were found between mouse and human NaCT with respect to their sensitivities to citric acid cycle intermediates as substrates for these transporters. Mouse NaCT had at least 20 - 800-fold higher affinity for these intermediates than human NaCT. At physiological plasma levels of citrate mouse NaCT is fully active, but its human counterpart is not. Replacement of extracellular sodium by other monovalent cations revealed that human NaCT was markedly less dependent on extracellular sodium than mouse NaCT. The low sensitivity of human NaCT for citrate raises questions about the translatability of this target from the mouse to the human situation and raises doubts about the validity of this transporter as a therapeutic target for the treatment of metabolic diseases in human beings.
- The American Society for Pharmacology and Experimental Therapeutics