Choline

NUTRIENT INFORMATION Choline1,2 Deficiencies: Healthy humans with normal folate and vitamin B-12 status who were fed a choline-deficient diet developed fatty liver, liver damage [elevated plasma alanine (or aspartate) transaminase] or developed muscle damage (elevated creatine phosphokinase) that resolved when choline was restored to the diet (4,6). Elevations in markers of DNA damage (7) and alterations in lymphocyte gene expression (8) were also observed in choline deficiency. During pregnancy, women in the lowest quartile of dietary choline intake had a higher risk of having a baby with a neural tube defect (NTD)3 or cleft palate (9,10). In rodent models, maternal dietary choline influences brain development in the fetus (11,12) and increases the prevalence of heart defects (13). Diet recommendations: In 1998, the U.S. Institute of Medicine’s Food and Nutrition Board established an Adequate Intake (AI) and a Tolerable Upper Limit (UL) for choline (14). The AI is 425 and 550 mg/d for women and men, respectively, with more recommended during pregnancy and lactation. The AI for infants is estimated from the calculated intake from human breast milk. Food sources: Choline and esters of choline are widely distributed in food; however, animal products generally contain more choline per unit weight than plants. Eggs, beef, chicken, fish, and milk as well as select plant foods like cruciferous vegetables and certain beans are particularly good sources of choline providing at least 10% of the daily requirement per serving (15–18). Humans consuming an ad libitum diet ingest between 150 and 600 mg choline/d as free choline and choline esters (10,19–23). In the 2005 NHANES 46 study, only a small portion of Americans in all age groups ate diets that met the recommended intake for choline (24). Foods also contain the choline metabolite betaine (17), which cannot be converted to choline but can be used as a methyl donor, thereby sparing some choline requirements (25,26). Plant-derived foods can be a rich source of betaine (named after beets), with grain products being particularly good sources. Clinical uses: Hepatic complications associated with total parenteral nutrition (TPN), which include fatty infiltration of the liver and hepatocellular damage, have been reported by many clinical groups. Frequently, TPN must be terminated because of the severity of the associated liver disease. Amino acid-glucose solutions used in TPN of humans contain no choline. The lipid emulsions used to deliver extra calories and essential fatty acids during parenteral nutrition contain choline in the form of phosphatidylcholine (20% emulsion contains 13.2 mmol/L). Some of the liver disease associated with TPN is related to choline deficiency and is prevented with supplemental choline or phosphatidylcholine (27–31). Thus, choline is an essential nutrient during long-term TPN. Toxicity: The UL for choline was derived from the lowest observed adverse effect level (hypotension) in humans and is 3.5 g/d for an adult (14). Recent research: Genetic variation likely underlies these differences in dietary requirements for choline. As discussed earlier, several metabolic pathways influence how much choline is required from diet, and single nucleotide polymorphisms in specific genes influence the efficiency of these pathways. Specifically, some polymorphisms in the folate pathways limit the availability of methyltetrahydrofolate and thereby increase the use of choline as a methyl donor, polymorphisms in the PEMT gene alter endogenous synthesis of choline, and polymorphisms in other genes of choline metabolism influence dietary requirements by changing the utilization of choline moiety (32,33). In men, intakes exceeding the choline AI are needed to optimize homocysteine disposal after a methionine load as well as the removal of fat from liver (34). A choline intake exceeding current dietary recommendations was also shown to preserve markers of cellular methylation and attenuate DNA damage in a genetic subgroup of folate-compromised men (35). Epidemiological studies have linked low dietary choline intake to higher concentrations of proinflammatory markers (36,37) as well as to increased risk of breast cancer (14) and to having a baby with a NTD (7). Elevated NTD risk was also associated with lower concentrations of serum total choline in a folate-fortified population (38). Additionally, genetic variants in choline metabolizing enzymes are associated with excess risk of NTD (39) and altered risk of breast cancer (40). A recent study in a mouse model of Down Syndrome reported improvements in cognitive function and emotion regulation in ©2010 American Society for Nutrition. Adv. Nutr. 1: 46–48, 2010; doi:10.3945/an.110.1010. Downloaded from https://academic.oup.com/advances/article/1/1/46/4657096 by guest on 07 January 2023 C holine has several important functions. It is a source of methyl groups needed to make the primary methyl donor, S-adenosylmethionine; a part of the neurotransmitter acetylcholine; and a component of the predominant phospholipids in membranes (phosphatidylcholine and sphingomyelin) (1). The choline derivative, phosphatidylcholine, is a main constituent of VLDL and is required for VLDL secretion and the export of fat from liver (2). Betaine, formed from choline, is an important osmolyte in the kidney glomerulus and helps with the reabsorption of water from the kidney tubule (3). The choline moiety can be produced endogenously when phosphatidylcholine is formed from phosphatidylethanolamine, mainly in the liver. Despite this capacity to form choline in liver, most men and postmenopausal women need to consume choline in their diets (4); the gene for the enzyme catalyzing this biosynthesis is induced by estrogen (5) and some young nonpregnant women may not need to eat choline (4). Genetic polymorphisms in genes of choline metabolism increase the dietary requirement for choline and almost one-half of young women have a gene polymorphism that makes choline biosynthesis unresponsive to estrogen, making these women’s dietary choline requirement similar to men’s. Table 1. Dietary Reference Intake values for choline Population AI for infants AI for children AI for females AI for pregnancy AI for lactation 1 AI UL 0–6 mo 125 mg/d, 18 mg/kg 150 mg/d 200 mg/d 250 mg/d 375 mg/d 550 mg/d 550 mg/d 400 mg/d 425 mg/d 450 mg/d 550 mg/d Not possible to establish1 6–12 mo 1–3 y 4–8 y 9–13 y 14–18 y $19 y 14–18 y $19 y All ages All ages 1000 mg/d 1000 mg/d 2000 mg/d 3000 mg/d 3500 mg/d 3000 mg/d 3500 mg/d Age-appropriate UL Age-appropriate UL Source of intake should be food and formula only. From (14). mice born to mothers supplemented with choline during the perinatal period (41). This work expands upon earlier work in rodents showing that extra exposure to choline during the perinatal period yielded long lasting beneficial effects on memory, learning and attention (42). Steven H. Zeisel* UNC Nutrition Research Institute, Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC 27599 Marie A. Caudill Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853 1 Supported by the NIH (grant no. DK55865 to the University of North Carolina Nutrition) and Obesity Research Center (grant no. DK56350) and Clinical and Translational Research Center (grant nos. M01RR00046 and UL1RR025747). 2 Author disclosures: S. H. Zeisel has no financial conflict of interest in relation to this manuscript. Dr. Zeisel received grant support from Mead Johnson Nutritionals, Balchem, and the Egg Nutrition Research Center for research studies and serves on an advisory board for Solae, Dupont, Western Almond Board, and Hershey. M. A. Caudill has no financial conflict of interest in relation to this manuscript. Dr. Caudill received grant support from the Egg Nutrition Research Center and from the Beef Checkoff through the National Cattlemen’s Beef Association and the Nebraska Beef Council. 3 Abbreviations used: AI, Adequate Intake; NTD, neural tube defect; TPN, total parenteral nutrition; UL, Tolerable Upper Limit. * To whom correspondence should be addressed. E-mail: steven_ zeisel@unc.edu. Literature Cited 1. Zeisel SH. Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr. 2006; 26:229–50. 2. Yao ZM, Vance DE. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem. 1988;263:2998–3004. 3. Kempson SA, Montrose MH. Osmotic regulation of renal betaine transport: transcription and beyond. Pflugers Arch. 2004; 449:227–34. 4. Fischer LM, daCosta K, Kwock L, Stewart P, Lu T-S, Stabler S, Allen R, Zeisel S. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 2007;85:1275–85. 5. Resseguie M, Song J, Niculescu MD, da Costa KA, Randall TA, Zeisel SH. Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J. 2007;21:2622–32. 6. da Costa KA, Badea M, Fischer LM, Zeisel SH. Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. Am J Clin Nutr. 2004; 80:163–70. 7. da Costa KA, Niculescu MD, Craciunescu CN, Fischer LM, Zeisel SH. Choline deficiency increases lymphocyte apoptosis and DNA damage in humans. Am J Clin Nutr. 2006;84:88–94. 8. Niculescu MD, da Costa KA, Fischer LM, Zeisel SH. Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007;86:230–9. 9. Shaw GM, Carmichael SL, Laurent C, Rasmussen SA. Maternal nutrient intakes and risk of orofacial clefts. Epidemiology. 2006;17:285–91. 10. Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol. 2004;160:102–9. 11. Craciunescu CN, Albright CD, Mar MH, Song J, Zeisel SH. Choline availability during embryonic development alters progenitor cell mitosis in developing mouse hippocampus. J Nutr. 2003;133:3614–8. 12. Mehedint M, Craciunescu C, Zeisel S. Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc Natl Acad Sci USA. 2010;107:12834–9. 13. Chan J, Deng L, Mikael LG, et al. Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice. Am J Clin Nutr. 2010;91:1035–43. 14. Institute of Medicine, National Academy of Sciences. Choline. Dietary reference intakes for folate, thiamin, riboflavin, niacin, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academies Press; 1998. p. 390–422. 15. Caudill M. Pre- and postnatal health: evidence of increased choline needs. J Am Diet Assoc. 2010;110:1198–206. 16. Agriculture Research Service U.S. Department of Agriculture. USDA National Nutrient Database for Standard Reference, Release 23. 2010 [cited 2010 Jul 27]. 17. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003;133:1302–7. 18. Zeisel SH, Mar M-H, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. Zeisel and Caudill 47 Downloaded from https://academic.oup.com/advances/article/1/1/46/4657096 by guest on 07 January 2023 AI for males Age 19. 20. 22. 23. 24. 25. 26. 27. 28. 29. 30. 48 Choline 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. long term parenteral nutrition and is associated with hepatic aminotransferase abnormalities. Clin Nutr. 1993;12:33–7. Misra S, Ahn C, Ament ME, Choi HJ, Jenden DJ, Roch M, Buchman AL. Plasma choline concentrations in children requiring long-term home parenteral nutrition: a case control study. JPEN J Parenter Enteral Nutr. 1999;23:305–8. da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 2006;20: 1336–44. Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH. Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. Proc Natl Acad Sci USA. 2005;102:16025–30. Veenema K, Solis C, Li R, et al. Adequate Intake levels of choline are sufficient for preventing elevations in serum markers of liver dysfunction in Mexican American men but are not optimal for minimizing plasma total homocysteine increases after a methionine load. Am J Clin Nutr. 2008;88:685–92. Shin W, Yan J, Abratte CM, Vermeylen F, Caudill MA. Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic subgroup of folate-compromised men. J Nutr. 2010;140:975–80. Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Stefanadis C. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. Am J Clin Nutr. 2008;87:424–30. Fargnoli JL, Fung TT, Olenczuk DM, Chamberland JP, Hu FB, Mantzoros CS. Adherence to healthy eating patterns is associated with higher circulating total and high-molecular-weight adiponectin and lower resistin concentrations in women from the Nurses’ Health Study. Am J Clin Nutr. 2008;88:1213–24. Shaw GM, Finnell RH, Blom HJ, et al. Choline and risk of neural tube defects in a folate-fortified population. Epidemiology. 2009;20:714–9. Enaw JO, Zhu H, Yang W, et al. CHKA and PCYT1A gene polymorphisms, choline intake and spina bifida risk in a California population. BMC Med. 2006;4:36. Xu X, Gammon MD, Zeisel SH, et al. Choline metabolism and risk of breast cancer in a population-based study. FASEB J. 2008;22:2045–52. Moon J, Chen M, Gandhy SU, et al. Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. Behav Neurosci. 2010;124:346–61. Meck WH, Williams CL. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav Rev. 2003;27:385–99. Downloaded from https://academic.oup.com/advances/article/1/1/46/4657096 by guest on 07 January 2023 21. J. Nutr. 2003;133:1302–1307. Erratum in: J Nutr. 2003;133: 2918–9. Fischer LM, Scearce JA, Mar MH, Patel JR, Blanchard RT, Macintosh BA, Busby MG, Zeisel SH. Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level. J Nutr. 2005;135:826–9. Xu X, Gammon MD, Zeisel SH, Bradshaw PT, Wetmur JG, Teitelbaum SL, Neugut AI, Santella RM, Chen J. High intakes of choline and betaine reduce breast cancer mortality in a population-based study. FASEB J. 2009;23:4022–8. Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G. Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. BMC Cardiovasc Disord. 2007;7:20. Cho E, Zeisel SH, Jacques P, Selhub J, Dougherty L, Colditz GA, Willett WC. Dietary choline and betaine assessed by foodfrequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr. 2006;83:905–11. Konstantinova SV, Tell GS, Vollset SE, Ulvik A, Drevon CA, Ueland PM. Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine in middle-aged and elderly men and women. Am J Clin Nutr. 2008;88:1663–9. Jensen HH, Batres-Marquez SP, Carriquiry A, Schalinske KL. Choline in the diets of the U.S. population: NHANES, 2003– 2004. FASEB J. 2007;21:lb219. Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004;80: 539–49. Dilger RN, Garrow TA, Baker DH. Betaine can partially spare choline in chicks but only when added to diets containing a minimal level of choline. J Nutr. 2007;137:2224–8. Buchman A, Dubin M, Moukarzel A, Jenden D, Roch M, Rice K, Gornbein J, Ament M. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology. 1995;22: 1399–403. Buchman AL, Ament ME, Sohel M, Dubin M, Jenden DJ, Roch M, Pownall H, Farley W, Awal M, Ahn C. Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebocontrolled trial. JPEN J Parenter Enteral Nutr. 2001;25:260–8. Buchman AL, Dubin M, Jenden D, Moukarzel A, Roch MH, Rice K, Gornbein J, Ament ME, Eckhert CD. Lecithin increases plasma free choline and decreases hepatic steatosis in long-term total parenteral nutrition patients. Gastroenterolog. 1992;102: 1363–70. Buchman AL, Moukarzel A, Jenden DJ, Roch M, Rice K, Ament ME. Low plasma free choline is prevalent in patients receiving