Regulation of choline transport and metabolism by solute carriers 44A

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Choline is an essential nutrient for all animals. Inside the cell, choline is metabolised into membrane phospholipids (phosphatydylcholine), neurotransmitters (acetylcholine) and an osmolyte (a regulator of fluid balance) and a methyl-group donor betaine. We study mechanisms that regulate the function of a choline-specific transporter Slc44A1, likely involved in all those processes except in the acetylcholine formation. We first established how this protein functions in animal cell culture and now we investigate its importance in the entire organisms. Since choline is intensively metabolised during embryonic development, we want to understand how Slc44A1 and/or other transporters sense what exact choline levels are needed at specific stages of development and for what purposes. Therefore we plan to firmly establish organ requirements for different choline products during mouse development, when choline is exclusively supplied by placenta, and at adult stages, when dietary choline supplementation is a critical regulator of choline metabolism. We predict that during early development, transport mechanisms by Slc44A1 would sense stringent demands for choline metabolites, because of a rapid membrane formation, DNA methylation and cellular volume regulation. We think that the production of betaine is however less critical for survival than the formation of membranes, therefore some choline could be spared for membranes under stages of choline deficiencies, by reducing choline transport activity of Slc44A1 in mitochondria when choline oxidation to betaine would be minimized if not prevented. In mammals, there are four other proteins of the Slc44A gene family but it is unknown if they function as choline transporters or have some different roles. In a long-term, we plan to unravel the function of the entire gene family, but will start with the second member-Slc44A2, which mouse homologue will be cloned, functionally expressed and its transport mechanisms compared with the function of Slc44A1.