The organic cation transporters 1 and 2 mediate ethanolamine cellular efflux and control systemic phosphatidylethanolamine level

The organic cation transporters (OCT) 1 on the basolateral membrane of enterocytes and hepatocytes, and OCT2 on the basolateral membrane of proximal tubular cells are essential in regulating systemic micronutrient levels, while also safeguarding tissues by preventing the buildup of potentially harmful endogenous metabolites, drugs, and xenobiotics. In the present work, we integrated in vivo comparative metabolomics and lipidomics analyses of serum from wild type (WT) and Oct1/2$^{-/-}$ mice with in vitro uptake measurements in HEK293 cells overexpressing OCT1 or OCT2, to identify and characterize novel endogenous substrates of OCT1/2. Among the significant metabolite changes, ethanolamine in the serum of Oct1/2$^{-/-}$ mice was approximately 70% lower than in WT mice. The ethanolamine influx K$_t$ mediated by OCT1/2$^{-/-}$ ranged from 7.6 ± 3.7 mmol/L (mouse Oct2) to 13.4 ± 8.1 mmol/L (mouse Oct1). OCT1/2 did not transport ethanolamine at physiologically relevant extracellular concentrations (10-100 μmol/L), suggesting that OCTs do not play a role in the hepatic/renal uptake of ethanolamine. Conversely, the release of ethanolamine by cells pre-exposed to ethanolamine at the extracellular concentration of 50 μmol/L was significantly greater in the presence of OCT1/2$^{-/-}$. Finally, the serum of the Oct1/2$^{-/-}$ mice was characterized by a stark elevation across phosphatidylethanolamine (PE) and lysoPE species, but not in phosphatidylcholine and diacylglycerol species. Taken together, our in vitro and in vivo data indicate that mouse Oct1 and Oct2 are essential for facilitating the exit step of free ethanolamine vectorial transport and indirectly control systemic phosphatidylethanolamine level.