Choline—At the Intersection of Brain Development and Heart Health

Dietary choline is a nutrient that varies in its essential nature depending on the age and metabolic status of the individual. An estimate of adequate intake of 425 mg/day (adult females) and 550 mg/day (adult males) was recommended by the Institute of Medicine approximately a decade ago based on prevention of liver dysfunction. Only 4% of adult females and 13% of adult males consume an adequate amount of choline (NHANES, 2005-2006). More-recent research underscores the critical function of choline as a methyl donor and constituent of numerous important biological processes.

Identification of gene polymorphisms will impact choline requirements. Emerging genetic evidence emphasizes the importance of choline in neurological development and maintenance of heart health, and suggests that its biological role has been underestimated. Further identification of genetic variations and of more-appropriate biomarkers among human populations may lead to reassessment of the essential nature of choline, including: a) modifications of dietary choline recommendations; b) changes in the food supply; and c) adjustments in lifestyles to ensure an adequate intake of choline, specifically targeting at-risk populations.

Choline is an essential nutrient, partially met by synthesis in the liver and a few other tissues. Choline is found in foods such as eggs, chicken liver, wheat germ, and human milk. Insufficient consumption of choline-rich foods as part of a blanced diet contributes to the poor choline status within the United States.

More than 10 years ago, FDA required folic acid fortification of cereal grains in an effort to reduce the risk of neural tube defects (NTDs). Since this public health intervention, the rate of NTDs dropped by 26% in the U.S. In Puerto Rico, the prevalence of NTDs declined more than 60% between 1996 and 2003, while folic acid consumption among the at-risk population increased by approximately 30%. More-recent statistics suggest an increase in NTDs in Puerto Rico, emphasizing the importance of campaigns of birth defect awareness and the health consequences of consumption of folic acid and possibly choline among women of childbearing age.

The significant need for choline is interrelated with folic acid and methionine. This interrelationship is linked through the methyl metabolic pathway, which is critical in brain development, reproductive success, and heart health. Perturbations of endogenous choline metabolism have been identified and clearly contribute to choline inadequacy. Notably, single nucleotide polymorphisms (SNPs) of phosphatidylenthanolamine N-methyltransferase (PEMT) and methylenetetrahydrofolate dehydrotase (MTHFD1) genes have functional consequences and impact choline requirements. Evidence indicates that among studied populations, approximately 74% present at least one allele for the PEMT SNP, and 63% present at least one allele for the MTHFD1 SNP (Zeisel, 2006, 2009).

The importance of these SNPs may be elevated when folic acid intake is inadequate (Ivanov, 2009). A recent study among 43 healthy premenopausal women evaluated the potential impact of genetic polymorphisms on biomarkers of choline status. The subjects were stratified based on genetic variants of PEMT and MTHFD1. Upon folic acid restriction, some variants had a greater impact on homocysteine and phosphotidylcholine metabolites. This small study suggested folic acid restriction, as observed in several animal model systems, may modify the influence of choline-relevant SNPs, depending on the pathways under consideration. The evidence supports the dynamic interactions of folic acid and choline and suggests individual dietary recommendations may vary depending on their functional SNPs of these important nutrients.

Importantly, estrogen enhances endogenous choline synthesis through induction of the PEMT gene. Forty-four percent of premenopausal women develop symptoms associated with choline deficiency. During pregnancy and lactation, when plasma estrogen levels increase approximately 60-fold, the additional choline synthesis is generally adequate to support normal in utero development of the unborn child and also to meet the needs of the breast-fed infant. Under these physiological conditions, choline is actively provided against a concentration gradient through the placenta-maternal circulation, via amniotic fluid, with a 10-fold increase of choline concentration over the maternal blood, and increased amounts in breast milk available for direct consumption (Zeisel, 2008).

Choline-deficiency studies with rodent models indicate the importance of folic acid during periconception. Adequate choline nutriture is critical for normal neural tube closure, and subsequent maintenance of homocysteine concentrations. These observations are supported by human epidemiological data which indicate an increased risk of NTDs when compared to lower extreme quartile for choline intake. Upon examination of the interrelated metabolic pathways and observations during dietary choline deficiency, the high demand for choline during pregnancy and lactation contributes to marked decreases in choline metabolites and resultant hypomethylation of DNA. This latter perturbation may alter numerous methylation processes and gene expressions in the developing child. These observations and clinical considerations may well indicate a need to reconsider dietary requirements for choline, especially under various physiological conditions in women and infants.

Diabetes and insulin insufficiency may contribute to neurological impairments, lead to cognitive decline, and possibly accelerate the risk or manifestation of dementia. There is evidence that failures of insulin signaling may affect specific receptor proteins that are located in cholinergic neurons of the central nervous system (Wang, 2009). It is intriguing to further explore the function of choline since the generation of acetylcholine, a critical neurotransmitter, via the rate-limiting enzyme choline acetyltransferase within neuronal bodies is dependent on substrate availability and the expression of this enzyme stimulated by insulin. Thus, the vital functional role of choline and its interaction with insulin may be critical in reducing the risk of neurodegenerative diseases associated with Alzheimer’s and diabetes. Equally important, some reports of type 1 diabetes indicate demyelination is a co-morbidity of the disease and integral to the neuropathological processes (Northam, 2009). Clearly, clinical research among humans that assesses and ultimately defines the function of choline as it relates to age-related memory loss and neurodegeneration among diabetics and the healthy population should be implemented to confirm these relationships.

The prenatal period of development is a window of future health. The significance of maternal dietary folic acid and choline and their influence on gene expression and infant development and memory performance among adults suggest that another major step in public health could include choline fortification of the food supply. Until there is additional and compelling evidence, it is incumbent upon food, medicine, and health professionals to support the population-based dietary recommendations on folic acid and choline.

References cited in this article are available from the authors.

Roger Clemens, Dr.P.H.,
Contributing Editor
[email protected]

Wayne Bidlack, Ph.D.,
Contributing Editor
[email protected]