CHOLINE, GENES AND LIVER HEALTH
An alarming proportion, 25% of the world’s population ( is currently thought to have Non-Alcoholic Fatty Liver Disease (NAFLD) (1) and the prevalence is estimated to be between 16 -32% among Indians. Recent studies also suggested that NAFLD not only affects obese but also non- obese Asians, commonly termed as the “ Asian Paradox”, and further this NAFLD phenotype is described as ‘lean NAFLD’. In the recent years, research evidence shows that humans eating low choline diets tend to develop fatty liver and liver damage. (2).
Figure.1 Global Prevalence of NAFLD
Choline was officially recognized as an essential nutrient by the Institute of Medicine (IOM) in 1998.(3) It is a source of methyl groups needed for many steps in metabolism. The body needs choline to preserve the structural integrity. In addition, choline is needed to produce acetylcholine, an important neurotransmitter for memory, mood, muscle control, and other brain and nervous system functions. Choline also plays important roles in modulating gene expression, cell membrane signaling, lipid transport and metabolism, and early brain development.(4)
Liver is an important organ for metabolism and storage of choline, and liver is dependent on a source of choline. Choline deficient diets, including those that are also deficient in methionine, have long been utilized to study the mechanisms of fatty liver disease and its progression because such diets recapitulate many of the phenotypes seen in humans with NAFLD, including an accumulation of triglycerides in the liver.
Humans can produce choline endogenously in the liver, mostly as phosphatidylcholine, with the help of enzyme phosphatidylethanolamine N-methyltransferase (PEMT) accounting to 30% of its synthesis in the liver, but the amount that the body naturally synthesizes is not sufficient to meet the requirements, so it needs to be obtained from the diet.(5)
There are two main metabolic routes for choline in the body: the exogenous and the endogenous. Choline is obtained in the form of phosphatidylcholine from the diet, that follows the same pathway as of the de novo biosynthesis where phosphatidylcholine is catalysed by phosphatidylethanolamine-N methyltransferase (PEMT) gene, through the methylation of phosphatidylethanolamine to Phosphatidylcholine. Choline is generated endogenously when the methylation of phosphatidylethanolamine is coupled with the catabolism of newly formed phosphatidylcholine by phospholipases.
Choline is converted into Phosphatidylcholine, while, in turn, phosphatidylcholine can be converted back into choline through the cytidine diphospho(CDP)-choline pathway. Ultimately choline can be converted to four different forms, one form of choline is converted into Acetylcholine. (6)
Choline, via its irreversible oxidation to betaine, methylates homocysteine to form methionine with the help of MTRR and MTHFR genes. This is the precursor for synthesis of S-adenosylmethionine, the universal methyl donor needed for methylation of DNA, RNA and proteins. It is important to realize that choline, methionine and folate metabolism is inter-related at the step that homocysteine is methylated to form methionine. (7) And excess of choline levels is converted to Trimethylamine N-oxide is generated from the oxidation of TMA that occurs in the gut microbiota, with the help of FMO3 gene that leads to risk of CVD.
METABOLISM OF CHOLINE
FOODS TO PROMOTE CHOLINE METABOLISM
Factors influencing choline requirements:
Estrogen moderates the dietary requirement for choline. Estrogen induces the gene (PEMT) that makes endogenous synthesis of choline possible. Thus, premenopausal women have an enhanced capacity for biosynthesis of choline.
Estradiol concentration rises during pregnancy, suggesting that capacity for endogenous synthesis of choline is highest during the period when females need to support fetal development.
When a diet is deficient in folate, a B-vitamin that is also a methyl donor, the need for dietary choline rises because choline becomes the primary methyl donor. And hence, genetic variants of genes in folate metabolism also modified the susceptibility of these subjects to choline deficiency. (14)
Genetic variation likely underlies these differences in dietary requirements.(15)
PEMT encodes for a protein responsible for endogenous formation of choline. Single Nucleotide Polymorphisms (SNPs) in this gene strongly influence dietary Choline demands. 78% of female carriers of the variant (C) allele in a SNP in the promoter region of the PEMT gene (rs12325817) developed organ dysfunction when fed a low choline diet as it marks a haplotype with decreased estrogen-responsive induction of PEMT.
Another SNP in the coding region of the choline dehydrogenase gene (CHDH; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (rs12676) was associated with increased susceptibility.(16) (17)
Premenopausal women who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-G1958A (MTHFD1; rs2236225) gene allele were more than 15 times as likely as non-carriers to develop signs of choline deficiency (p < 0.0001) on the low choline diet, thereby increasing the demand for choline as a methyl-group donor. It is of interest that the risk of having a child with a neural tube defect increases in mothers with the rs 2236225 SNP.18
Knowledge of interactions between genetic variants and select nutrients offers the potential to customize dietary recommendations at the individual level (i.e., personalized nutrition) and to ensure that population based dietary recommendations are sufficient for those with the highest needs.
Author Bio: Rashida Kadanawala, is a Clinical Dietitian Trainer, at Administration of Food and Nutrition, Ministry of health, Kuwait for over 7 years. Besides her role in training dietitians and developing programs; her zest lies in nutrition consultation and education in hospital and community settings. Rashida believes in empowering dietitians with evidence-based practice and offer best personalized Nutrition for patients, which is possible through Nutrigenetics. She focuses on staying fit by lifting weights, taking walks, yoga and eating real food. Her passion is to explore various aspects of Nutrition Science and she believes continuous learning and sharing is the only way to grow in all ventures. Rashida, an Indian by nationality, loves exploring new corners of the world, especially if they include a good wave to surf or a nice slope to descend.