Human Requirements for the Nutrient Choline

人类对营养胆碱的需求

• 批准号: 7898262
• 负责人: Steven H Zeisel
• 金额: $ 10万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898262
• 关键词: Address; Affect; Alleles; Anabolism; Betaine; Cell membrane; Choline; Choline Deficiency; Choline dehydrogenase; Clinical Research; Diet; Dihydrofolate Reductase; Enzymes; Estrogens; Fatty Liver; Female; Functional disorder; Funding; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Human; Individual; Institute of Medicine (U.S.); Intake; Lecithin; Metabolism; Methyltransferase; Methyltransferase Gene; Muscle; Neural Tube Defects; Nutrient; Nutritional Requirements; Odds Ratio; Organ; Phosphatidylethanolamine; Phosphatidylethanolamine N-Methyltransferase; Population; Population Heterogeneity; Postmenopause; Predisposition; Premenopause; Prevalence; Promoter Regions; Recommendation; Recruitment Activity; Resistance; Risk; Signal Transduction; Single Nucleotide Polymorphism; Source; Variant; Woman; base; carbene; choline deficient diet; cholinergic; dietary requirement; feeding; folic acid metabolism; gain of function; interest; lipid transport; loss of function; membrane synthesis; men; methyl group; neurotransmission; oxidation; phosphatidylethanolamine; prevent; promoter; research study

DESCRIPTION (provided by applicant): Choline is a dietary nutrient essential for the structural integrity and signaling functions of cell membranes; it is the major source of methyl-groups in the diet, and it directly affects cholinergic neurotransmission, transmembrane signaling and lipid transport/metabolism. The major premise for this proposal is that humans require a dietary source of choline and that this requirement has significant individual variation. We suggest that estrogen and common genetic polymorphisms modulate this dietary requirement for choline. During the last 4 years of funding we established that 77% of men and 80% of postmenopausal women, when deprived of dietary choline, developed fatty liver or muscle damage. Only 43% of premenopausal women developed signs of organ dysfunction associated with choline deficiency. Some men developed such signs of choline deficiency when ingesting the presumed Adequate Intake for choline (550 mg/day). We observed that the PEMT promoter is estrogen responsive, and we hypothesize that estrogen status influences the dietary requirement for choline. We identified common genetic variations that appear to increase the likelihood that a human will become choline deficient when fed a low choline diet; postmenopausal women with a common single nucleotide polymorphism (snp) in the promoter region of the gene responsible for endogenous biosynthesis of choline (phosphatidylethanolamine N-methyltransferase, PEMT; rs12325817) had a odds ratio (OR) compared to wild type of 42 for developing signs of organ dysfunction when we removed choline from their diets (p=0.03); premenopausal women with a G78T snp in choline dehydrogenase had an OR of 20 (p=0.04) and premenopausal women with a common snp in methylene tetrahydrofolate dehydrogenase (MTHFD1-1958A) had an OR of >85 (p=.0001) for developing signs of choline deficiency. We identified another snp in choline dehydrogenase A40 that was associated with a decreased susceptibility to developing signs of choline deficiency in all subjects (OR = 0.2; p = 0.03). These snps are common in humans, for example, for the PEMT promoter snp 18% of our subjects were homozygous for the snp, 56% were heterozygous, and 26% were wild type. Therefore, it is important that we have a better understanding of how these genetic polymorphisms influence the dietary requirement for choline. We propose studies that will extend our observations during the last funding period and that will refine our understanding of factors that influence dietary requirements for choline in humans. Experiments are proposed that will determine whether postmenopausal women treated with estrogen have a lower choline requirement, identify functionally important SNPs, determine prevalence of these in the population and examine dietary choline requirements in humans with these SNPs.

描述（由申请人提供）：胆碱是细胞膜结构完整性和信号传导功能必不可少的饮食营养素。它是饮食中甲基组的主要来源，它直接影响胆碱能神经传递，跨膜信号传导和脂质转运/代谢。该提议的主要前提是人类需要饮食中的胆碱来源，并且该要求具有显着的个体差异。我们建议雌激素和常见的遗传多态性调节胆碱的饮食需求。在过去的四年资金中，我们确定了77％的男性和80％的绝经后妇女（当缺乏饮食中的胆碱）会产生脂肪肝或肌肉损害。只有43％的绝经前女性出现了与胆碱缺乏有关的器官功能障碍的迹象。一些男人在摄入假定的胆碱摄入量时会出现这种胆碱缺乏症的迹象（550 mg/天）。我们观察到PEMT启动子具有雌激素反应，并且假设雌激素状态会影响胆碱的饮食需求。我们确定了常见的遗传变异，这些变异似乎增加了喂养低胆碱饮食时人类会变得不足的可能性。在基因的启动子区域中具有常见单核苷酸多态性（SNP）的绝经后妇女，负责胆碱内源性生物合成（磷酸二甲醇N-甲基转移酶，pemt; rs12325817）的内源性生物合成;从他们的饮食中（p = 0.03）；在胆碱脱氢酶中具有G78T SNP的绝经前女性具有20（p = 0.04）和甲基甲基四氢叶酸甲基甲基甲基脱氢酶（MTHFD1-1958A）中常见的SNP的20（p = 0.04），而有> 85（p = .0001）的甲基甲基脱氢酶（MTHFD1-1958A），用于开发choline of choline defitiedils of choline defely sagoline faroline deficiation。我们在胆碱脱氢酶A40中确定了另一个SNP，这与在所有受试者中易感性降低有关（OR = 0.2; p = 0.03）的易感性降低。这些SNP在人类中很常见，因为PEMT启动子SNP的18％对SNP纯合为纯合，56％是杂合的，而26％的野生类型为野生。因此，重要的是，我们对这些遗传多态性如何影响胆碱的饮食需求有更好的了解。我们提出的研究将在最后一个资金期间扩展我们的观察结果，这将完善我们对影响人类胆碱饮食需求的因素的理解。提出了实验，该实验将确定用雌激素治疗的绝经后妇女是否具有较低的胆碱需求，识别功能上重要的SNP，确定这些SNP的人群中这些胆碱的患病率，并检查人群中的饮食胆碱需求。