Regulation of choline transport and metabolism by solute carriers 44A

溶质载体 44A 对胆碱转运和代谢的调节

• 批准号: 239209-2010
• 负责人: Bakovic, Marica
• 金额: $ 2.19万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=506581
• 关键词: Regulation; choline; transport; metabolism; solute

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.

胆碱是所有动物必需的营养物质。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)、渗透剂(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蛋白SLc44A1的功能的机制，该转运蛋白可能参与了除乙酰胆碱形成之外的所有这些过程。我们首先确定了这种蛋白质如何在动物细胞培养中发挥作用，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期间是密集代谢的，我们想要了解Slc44A1和/或其他转运蛋白如何感知特定发育阶段所需的确切胆碱水平，以及用于什么目的。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，当饮食中补充胆碱是胆碱代谢的关键调节因素时，确定不同胆碱产品的器官需求。我们预测，在发育早期，Slc44A1的运输机制将感受到对胆碱代谢物的严格需求，因为快速的膜形成、DNA甲基化和细胞体积调节。然而，我们认为甜菜碱的产生对生存的关键没有膜的形成那么关键，因此，在胆碱缺乏阶段，可以通过降低线粒体内SLc44A1的胆碱运输活性来节省一些胆碱，因为此时胆碱氧化为甜菜碱的作用即使不被阻止，也会被最小化。在哺乳动物中，SLc44A基因家族还有其他四种蛋白，但尚不清楚它们是作为胆碱转运蛋白发挥功能，还是具有一些不同的作用。从长远来看，我们计划解开整个基因家族的功能，但将从第二个成员Slc44A2开始，该成员将克隆、功能表达小鼠同源物，并与Slc44A1的功能进行比较。