• Leo Rex

Choline: An Essential and Dangerous Nutrient

This series of two articles is speculative. It is not written by a medical professional and does not present medical advice. Consult with your provider before changing any aspect of your lifestyle or diet.


The first article in this series summarizes the nutritional value of choline and the danger associated with its dietary consumption. The second article in this series presents a solution to the predicament.


To watch the companion video to this series, click here.


CHOLINE IS A VITAMIN


Choline deficiency causes cellular apoptosis[1][2]. It is also the only known nutritional deficiency that directly causes cancer in the absence of carcinogens[3][4] - specifically, it causes hepatocellular carcinoma. Despite these metabolic effects being known by the 1980’s, it was not until the late 1990’s that choline was recognized as an essential nutrient. Essential nutrients, many of which are called vitamins, are classically defined by a clear and consistent pathology that develops in a deficiency state.


In the case of choline, the pathology takes the form of fatty liver disease and steatosis of the liver. Studies on people fed parenteral nutrition (liquid nutrition given intravascularly) by Alan Buchman revealed that patients lacking choline in their diet developed fatty liver disease that would progress to steatosis within weeks. When choline was added back to the diet, the liver would heal and return to normal function[5].


For a more detailed review on the academic discovery of the essential role of dietary choline, read my article here.


CHOLINE, METHYLATION, AND HEALTH


The most well-known impact of the proliferation of genome wide association studies in public discourse has been the recognition that humans have widely varying abilities to methylate molecules. Methylation, also called one-carbon metabolism, is an integral biochemical process by which molecules are transformed structurally. In the major methylation pathway, homocysteine is recycled back into methionine through methylation. People with polymorphisms at the PEMT, MTHFD1[6], BHMT[7][8], MTHFR[9], MTR, MTRR[10], SLC19A1[11], COMT[12], and SHMT1[13] genes may have impaired ability to methylate molecules.


When methylation is impaired, blood homocysteine levels remain elevated – a condition known as hyperhomocysteinemia. Hyperhomocysteinemia is strongly associated with atherosclerosis, heart failure, and Alzheimer’s disease[14]. For people with impaired ability to methylate (particularly at the notorious MTHFR gene[15]), a prudent way to reduce the methylation demands on their body includes supplementing with creatine and phosphatidylcholine. In particular, the synthesis of phosphatidylcholine from phosphatidylethanolamine via the liver enzyme phosphatidylethanolamine N-methyltransferase (PEMT) comprises a large portion of the methylation demands of the human body [16].


By reducing demands on the methylation system and allowing the body to metabolize homocysteine, dietary consumption of phosphatidylcholine may reduce risks of cardiovascular and neurodegenerative disease[17]. Polymorphisms that impair methylation are also associated with depression[18][19], anxiety[20][21], and cognitive function[22][23][24][25], as is the resulting condition, hyperhomocysteinemia[26]. Consequently, it is reasonable to speculate that phosphatidylcholine supplementation may improve well-being and cognitive performance[27], in addition to cardiovascular health.


CHOLINE THE NEUROTRANSMITTER


In addition to choline’s roles in cellular health, liver health, cardiovascular health, and mental health, choline plays a crucial role in cognitive performance via the neurotransmitter acetylcholine. Acetylcholine is synthesized from dietary choline. It is such an impactful neurotransmitter on memory and learning that the primary symptom-management medications for Alzheimer’s disease are inhibitors of the enzyme that degrades acetylcholine in the brain, acetylcholinesterase.


As I have written a series of articles on acetylcholine, which you can access here, I will not get into the details of the neuroscience of acetylcholine in this article. For our purposes, it is sufficient to recognize that nutritional choline plays an important role in brain function.


THE PROBLEM WITH EATING CHOLINE


Unlike the other major reducer of methylation demands, creatine, the consumption of dietary choline comes with a cost. Though dietary choline is associated with a lower risk of stroke[28], lower mortality from cardiovascular disease[29], lower inflammatory markers (including C-reactive protein, interleukin-6, and tumor necrosis factor alpha)[30], in 2011, it was discovered that the metabolism of phosphatidylcholine by gut microbiota could present significant cardiovascular disease risk[31].


In one of the most cited papers of the last decade, Wang et al. showed that gut microbiota cleave trimethylamine (TMA) from dietary phosphatidylcholine, subsequent to which TMA is oxidized by the liver enzyme flavin monooxygenase 3 (FMO3) into trimethylamine N-oxide (TMAO). The research team found that systemic TMAO levels were strongly associated with atherosclerosis and cardiac risk. Subsequent studies have confirmed these initial findings[32] and linked TMAO to venous thrombosis[33], diabetes[34] and colorectal cancer[35]. (Interestingly, rodent studies indicate that androgens may reduce systemic TMAO by reducing the expression of the enzyme FMO3[36], while resveratrol has been shown to reduce TMAO by remodeling the gut microbiome[37]).


The predicament with TMAO was most prominently introduced to public discourse in a well-publicized debate between a vegan and an omnivore on the Joe Rogan Experience podcast. Subsequently, vegans have used the TMAO argument to encourage the public to reduce their consumption of animal products, which often contain both choline and L-carnitine, a nutrient found in red meat that was also shown to be metabolized into TMAO by the same research team[38]. Though not the subject of this article, it is worthwhile to note that L-carnitine has also been shown to improve cognitive function in neurodegenerative disease models[39] and is one of the only methods that has been shown to reduce plasma lipoprotein (a) levels[40], a major risk factor for cardiovascular disease.


To read the second and final article in this series, click here.

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Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology, 22(5), 1399-1403. [6] Ivanov, A., Nash-Barboza, S., Hinkis, S., & Caudill, M. A. (2009). Genetic variants in phosphatidylethanolamine N-methyltransferase and methylenetetrahydrofolate dehydrogenase influence biomarkers of choline metabolism when folate intake is restricted. Journal of the American Dietetic Association, 109(2), 313-318. [7] Huang, X., Li, D., Zhao, Q., Zhang, C., Ren, B., Yue, L., ... & Zhang, W. (2019). Association between BHMT and CBS gene promoter methylation with the efficacy of folic acid therapy in patients with hyperhomocysteinemia. Journal of Human Genetics, 64(12), 1227-1235. [8] Teng, Y. W., Mehedint, M. G., Garrow, T. A., & Zeisel, S. H. (2011). Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas. Journal of Biological Chemistry, 286(42), 36258-36267. [9] Yan, J., Wang, W., Gregory III, J. F., Malysheva, O., Brenna, J. T., Stabler, S. P., ... & Caudill, M. A. (2011). MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline. The American journal of clinical nutrition, 93(2), 348-355. [10] Li, W. X., Dai, S. X., Zheng, J. J., Liu, J. Q., & Huang, J. F. (2015). Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency. Nutrients, 7(8), 6670-6687. [11] Stanisławska‐Sachadyn, A., Mitchell, L. E., Woodside, J. V., Buckley, P. T., Kealey, C., Young, I. S., ... & Strain, J. J. (2009). The reduced folate carrier (SLC19A1) c. 80G> A polymorphism is associated with red cell folate concentrations among women. Annals of human genetics, 73(5), 484-491. [12] Goodman, J. E., Lavigne, J. A., Wu, K., Helzlsouer, K. J., Strickland, P. T., Selhub, J., & Yager, J. D. (2001). COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk. Carcinogenesis, 22(10), 1661-1665. [13] Succi, M., de Castro, T. B., Galbiatti, A. L. S., Arantes, L. M. R. B., da Silva, J. N. G., Maniglia, J. V., ... & Goloni-Bertollo, E. M. (2014). DNMT3B C46359T and SHMT1 C1420T polymorphisms in the folate pathway in carcinogenesis of head and neck. Molecular biology reports, 41(2), 581-589. [14] Kim, J., Kim, H., Roh, H., & Kwon, Y. (2018). Causes of hyperhomocysteinemia and its pathological significance. Archives of pharmacal research, 41(4), 372-383. [15] Tanaka, T., Scheet, P., Giusti, B., Bandinelli, S., Piras, M. G., Usala, G., ... & Sofi, F. (2009). Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. The American Journal of Human Genetics, 84(4), 477-482. [16] Brosnan, J. T., Jacobs, R. L., Stead, L. M., & Brosnan, M. E. (2004). Methylation demand: a key determinant of homocysteine metabolism. Acta Biochimica Polonica, 51(2), 405-413. [17] E Smith, R., Rouchotas, P., & Fritz, H. (2016). Lecithin (Phosphatidylcholine): Healthy dietary supplement or dangerous toxin?. The Natural Products Journal, 6(4), 242-249. [18] Różycka, A., Słopień, R., Słopień, A., Dorszewska, J., Seremak-Mrozikiewicz, A., Lianeri, M., ... & Drews, K. (2016). The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women. Maturitas, 84, 42-54. [19] Rai, V. (2017). Association of C677T polymorphism (rs1801133) in MTHFR gene with depression. Cell Mol Biol (Noisy-le-grand), 63(6), 60-67. [20] Panitz, C., Sperl, M. F., Hennig, J., Klucken, T., Hermann, C., & Mueller, E. M. (2018). Fearfulness, neuroticism/anxiety, and COMT Val158Met in long-term fear conditioning and extinction. Neurobiology of learning and memory, 155, 7-20. [21] Jiménez, K. M., Pereira-Morales, A. J., & Forero, D. A. (2018). MTHFR gene methylation is associated with perceived stress in healthy young adults. Psychiatric Genetics, 28(3), 41-46. [22] Wang, W., Fan, W., Shi, B., Tong, C., Wang, X., Cai, J., & Zhang, C. (2017). Effect of MTHFR gene on the schizophrenia and its cognitive function. Zhonghua yi xue yi Chuan xue za zhi= Zhonghua Yixue Yichuanxue Zazhi= Chinese Journal of Medical Genetics, 34(6), 905-908. [23] Bahous, R. H., Cosín-Tomás, M., Deng, L., Leclerc, D., Malysheva, O., Ho, M. K., ... & Rozen, R. (2019). Early manifestations of brain aging in mice due to low dietary folate and mild MTHFR deficiency. Molecular neurobiology, 56(6), 4175-4191. [24] Matsuzaka, C. T., Christofolini, D., Ota, V. K., Gadelha, A., Berberian, A. A., Noto, C., ... & Melaragno, M. I. (2017). Catechol-O-methyltransferase (COMT) polymorphisms modulate working memory in individuals with schizophrenia and healthy controls. Brazilian Journal of Psychiatry, 39(4), 302-308. [25] Mestrovic, A. H., Tudor, L., Perkovic, M. N., Erjavec, G. N., Petrovic, Z. K., Strac, D. S., ... & Pivac, N. (2018). Significant association between catechol-O-methyltransferase (COMT) Val158/108Met polymorphism and cognitive function in veterans with PTSD. Neuroscience letters, 666, 38-43. [26] Kolling, J., Longoni, A., Siebert, C., Dos Santos, T. M., Marques, E. P., Carletti, J., ... & Wyse, A. T. (2017). Severe hyperhomocysteinemia decreases creatine kinase activity and causes memory impairment: neuroprotective role of creatine. Neurotoxicity Research, 32(4), 585-593. [27] Poly, C., Massaro, J. M., Seshadri, S., Wolf, P. A., Cho, E., Krall, E., ... & Au, R. (2011). The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. The American journal of clinical nutrition, 94(6), 1584-1591. [28] Millard, H. R., Musani, S. K., Dibaba, D. T., Talegawkar, S. A., Taylor, H. A., Tucker, K. L., & Bidulescu, A. (2018). 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R., Muntner, P., ... & Lip, G. Y. (2016). Impact of L-carnitine on plasma lipoprotein (a) concentrations: A systematic review and meta-analysis of randomized controlled trials. Scientific reports, 6, 19188.

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