Laboratory Head Institute of Experimental and Clinical Pharmacology and Toxicology
Department of Clinical Pharmacology and Clinical Toxicology
Friedrich–Alexander University Erlangen–Nürnberg Erlangen, Germany
At present, the SLC transporter superfamily (SLC = solute carrier) comprises more than 450 transport proteins belonging to 65 different families. Transport proteins of this superfamily are important for the uptake of endogenous substances and xenobiotics from the extracellular space into cells and more than 80 transporters have been linked to human diseases including type 2 diabetes and obesity. The SLC13 gene family of sodium-coupled di- and tricarboxylate transporters consists of five human members (NaSi1, NaDC2, NaDC3, NaSUT1 and NaCT) with orthologues found in prokaryotes and eukaryotes. The human uptake transporter NaCT (sodium-coupled citrate transporter, gene symbol SLC13A5) is expressed in brain and the basolateral membrane of hepatocytes. NaCT is the human orthologue of the Drosophila Indy transporter (Indy = I´m not dead yet) and mediates the uptake of citrate and other intermediates of the tricarboxylic acid cycle (TCA cycle) from blood into hepatocytes and neurons. Studies in Drosophila and Caenorhabditis have demonstrated that reduced expression of NaCT promotes longevity probably due to caloric restriction. Long-lived flies showed reduced body fat stores, a lower expression of insulin-like proteins and an increase in mitochondrial number. Studies with NaCT(-/-) knock out mice demonstrated that deletion of this transporter mimics aspects of dietary restriction and protects these mice against adiposity and insulin resistance. Furthermore, NaCT seems to be important for the development and the function of the human brain because mutations in the SLC13A5 gene encoding human NaCT are associated with epileptic encephalopathies, a group of severe disorders characterized by psychomotor delay, abnormal electro-encephalograms and seizures. Recently it has been demonstrated that alterations in brain citrate levels due to reduced or absent NaCT transport function result in neuronal network excitability and increased seizure propensity. This presentation will provide an overview on human NaCT in glucose and energy metabolism and will highlight the potential role of this transporter as therapeutic target for the treatment of type 2 diabetes, obesity and non-alcoholic fatty liver disease. Furthermore, studies on the functional consequences of mutations in the SLC13A5 gene encoding NaCT leading to epileptic encephalopathy will be presented.
understand the role of transport proteins for energy metabolism
discuss the importance of the uptake transporter NaCT for metabolic diseases
understand the functional consequences of mutations in the SLC13A5 gene encoding human NaCT