Electrophysiological characterization of human and mouse sodium-dependent citrate transporters (NaCT/SLC13A5) reveal species differences with respect to substrate sensitivity and cation dependence

The Journal of Pharmacology and Experimental Therapeutics
Ruud ZwartEmanuele Sher

Abstract

The citric acid cycle intermediate citrate plays a crucial role in metabolic processes such as 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; therefore, NaCT has been proposed as an attractive therapeutic target for the treatment of obesity and type 2 diabetes. In this study, we 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- to 800-fold higher affinity for these intermediates than human NaCT. Mouse NaCT is fully active at physiologic plasma levels of citrate, 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 qu...Continue Reading

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Citations

Jan 31, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Christian von LoeffelholzAndreas L Birkenfeld
Mar 11, 2020·The Journal of Biological Chemistry·Ahlam KhamaysiEhud Ohana
Apr 14, 2016·CPT: Pharmacometrics & Systems Pharmacology·Z LiT S Maurer

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