Regulation of choline transport and metabolism by solute carriers 44A

胆碱是所有动物必需的营养素。在细胞内，胆碱被代谢成膜磷脂（磷脂酰胆碱）、神经递质（乙酰胆碱）、渗透物（液体平衡调节剂）和甲基供体甜菜碱。我们研究了调节胆碱特异性转运体Slc44A1功能的机制，该转运体可能参与除乙酰胆碱形成外的所有这些过程。我们首先确定了这种蛋白质在动物细胞培养中的作用，现在我们研究它在整个生物体中的重要性。由于胆碱在胚胎发育过程中被大量代谢，我们想要了解Slc44A1和/或其他转运蛋白是如何感知特定发育阶段所需的胆碱水平以及出于何种目的。因此，我们计划在小鼠发育期间，当胆碱完全由胎盘供应时，以及在成年阶段，当饮食胆碱补充是胆碱代谢的关键调节剂时，牢固地建立对不同胆碱产品的器官需求。我们预测，在早期发育过程中，由于膜的快速形成、DNA甲基化和细胞体积调节，Slc44A1的转运机制将感知对胆碱代谢物的严格需求。然而，我们认为甜菜碱的产生对生存的重要性不如膜的形成，因此，在胆碱缺乏的阶段，通过降低线粒体中Slc44A1的胆碱运输活性，胆碱氧化成甜菜碱将被最小化，如果不阻止的话，胆碱可以被保留在膜上。在哺乳动物中，Slc44A基因家族中还有其他四种蛋白质，但它们是否作为胆碱转运蛋白或具有其他作用尚不清楚。从长远来看，我们计划揭开整个基因家族的功能，但将从第二个成员slc44a2开始，克隆其小鼠同源物，功能表达及其与Slc44A1功能的转运机制比较。

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.