The SLC13 family comprises five family members. [SLC13A2 (NaDC1), SLC13A3 (NaDC3), and SLC13A5 (NaCT)] co-transports, NaS1 and NaS2.
Sodium-coupled citrate transporter (NaCT) and NaDC1 and NaDC3 are responsible for transporting cellular anionic intermediates. For example, citrate can promote de novo lipogenesis (DNL) and promote the flux of glycolysis through allosteric interactions with phosphofructokinase (PFK).
Citrate from the blood into the cells where these intermediates can serve as energy sources.
In this article, we will introduce a sodium-coupled citrate transporter inhibitor, PF-06649298.
This compound specifically inhibits the transport of citrate in human hepatocytes. PF-06649298 shows interaction with NaCT with IC50 value of 16.2 μM. PF-06649298 (0-100 μM; 30 min) inhibits citrate uptake in HEK-293 cells expressing NaCT, NaDC1, or NaDC3, as well as human hepatocytes and mouse epatocytes.
PF-06649298 shows selectivity for NaCT over the dicarboxylate transporters NaDC1 and NaDC3. Additionally, it inhibits citrate uptake in HEK-293 cells expressing NaCT with an IC50 of 408 nM, while the IC50s are ＞100 μM, ＞100 μM, 16.2 μM and 4.5 μM in HEK-293 cells expressing NaDC1 or NaDC3, as well as human hepatocytes and mouse hepatocytes, respectively.
Furthermore, PF-06761281 is a potent inhibitor with a suitable in vivo pharmacokinetic profile for the assessment of in vivo pharmacodynamics. It demonstrates a dose-dependent inhibition of radioactive [(14)C]citrate uptake in the liver and kidney in vivo. Besides, it results in modest reductions in plasma glucose concentrations.
In the high-fat diet (HFD) mice model, PF-06649298 (250 mg/kg; p.o. twice a day; for 21 days) totally reverses the glucose intolerance of HFD mice. Moreover, It decreases plasma glucose, hepatic triglycerides, diacylglycerides, and acyl-carnitines concentration in livers in HFD mice.
Inhibition of NaCT acts as a new therapeutic approach for the prevention and treatment of metabolic diseases. As a result, PF-06649298 can be used for the research of regulating glucose metabolism and lipid metabolism.