Model-Based Assessment of Plasma Citrate Flux Into the Liver: Implications for NaCT as a Therapeutic Target.

Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium-coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical information necessary to underwrite confidence in this target. In this work, hepatic influx of plasma citrate was quantified via pharmacokinetic modeling of published clinical data. The influx was then compared to independent literature estimates of intracellular citrate flux in human liver. The results indicate that, under normal conditions, <10% of hepatic citrate originates from plasma. Similar estimates were determined experimentally in mice and rats. This suggests that NaCT inhibition will have a limited impact on hepatic citrate concentrations across species. [ABSTRACT FROM AUTHOR]