Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.

Abstract

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.