Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cellular and organismal function of choline metabolism

Nature Metabolism volume 7, pages 35–52 (2025)Cite this article

Subjects

Abstract

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Chemistry of choline and its derived metabolites.
Fig. 2: Choline metabolism in mammalian cells.
Fig. 3: Organismal choline metabolism.
Fig. 4: Outstanding questions in choline metabolism.

Similar content being viewed by others

References

  1. Strecker, A. Ueber einige neue Bestandtheile der Schweinegalle. Justus Liebigs Ann. Chem. 123, 353–360 (1862).

    Google Scholar 

  2. Zeisel, S. H. A brief history of choline. Ann. Nutr. Metab. 61, 254–258 (2012).

    CAS  PubMed  Google Scholar 

  3. Li, Z. & Vance, D. E. Phosphatidylcholine and choline homeostasis. J. Lipid Res. 49, 1187–1194 (2008).

    CAS  PubMed  Google Scholar 

  4. Gobley, T. Recherches Chimiques Sur Les Oeufs de Carpe, Lues à l’Académie Nationale de Médecine (Imprimé par E. Thunot, 1850).

  5. Gobley, T. Sur La Lécithine et La Cérébrine (1874).

  6. Hensing, J. T. The discovery of lecithin, the first phospholipid. Bull. Hist. Chem. 29, 9–15 (2004).

    Google Scholar 

  7. Kennedy, E. P. & Weiss, S. B. The function of cytidine coenzymes in the biosynthesis of phospholipides. J. Biol. Chem. 222, 193–214 (1956).

    CAS  PubMed  Google Scholar 

  8. Hershey, J. M. & Soskin, S. Substitution of ‘lecithin’ for raw pancreas in the diet of the depancreatized dog. Am. J. Physiol. 98, 74–85 (1931).

    CAS  Google Scholar 

  9. Best, C. H. & Huntsman, M. E. The effects of the components of lecithine upon deposition of fat in the liver. J. Physiol. 75, 405–412 (1932).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Best, C. H. & Huntsman, M. E. The effect of choline on the liver fat of rats in various states of nutrition. J. Physiol. 83, 255–274 (1935).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Buchman, A. L. et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22, 1399–1403 (1995).

    CAS  PubMed  Google Scholar 

  12. Fischer, L. M. et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am. J. Clin. Nutr. 85, 1275–1285 (2007).

    CAS  PubMed  Google Scholar 

  13. Resseguie, M. E. et al. Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction. J. Biol. Chem. 286, 1649–1658 (2011).

    CAS  PubMed  Google Scholar 

  14. Zeisel, S. H. et al. Choline, an essential nutrient for humans. FASEB J. 5, 2093–2098 (1991).

    CAS  PubMed  Google Scholar 

  15. Tayek, J. A., Bistrian, B., Sheard, N. F., Zeisel, S. H. & Blackburn, G. L. Abnormal liver function in malnourished patients receiving total parenteral nutrition: a prospective randomized study. J. Am. Coll. Nutr. 9, 76–83 (1990).

    CAS  PubMed  Google Scholar 

  16. Chawla, R. K., Berry, C. J., Kutner, M. H. & Rudman, D. Plasma concentrations of transsulfuration pathway products during nasoenteral and intravenous hyperalimentation of malnourished patients. Am. J. Clin. Nutr. 42, 577–584 (1985).

    CAS  PubMed  Google Scholar 

  17. Burt, M. E., Hanin, I. & Brennan, M. F. Choline deficiency associated with total parenteral nutrition. Lancet 2, 638–639 (1980).

    CAS  PubMed  Google Scholar 

  18. Sheard, N. F., Tayek, J. A., Bistrian, B. R., Blackburn, G. L. & Zeisel, S. H. Plasma choline concentration in humans fed parenterally. Am. J. Clin. Nutr. 43, 219–224 (1986).

    CAS  PubMed  Google Scholar 

  19. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (National Academies Press, 1998); https://doi.org/10.17226/6015

  20. European Food Safety Authority. Dietary reference values for choline. EFSA J.14, 4484 (2016).

  21. Tavasoli, M., Lahire, S., Reid, T., Brodovsky, M. & McMaster, C. R. Genetic diseases of the Kennedy pathways for membrane synthesis. J. Biol. Chem. 295, 17877–17886 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Harayama, T. & Riezman, H. Understanding the diversity of membrane lipid composition. Nat. Rev. Mol. Cell Biol. 19, 281–296 (2018).

    CAS  PubMed  Google Scholar 

  23. Kennedy, E. P. Sailing to Byzantium. Annu. Rev. Biochem. 61, 1–28 (1992).

    CAS  PubMed  Google Scholar 

  24. Gallego-Ortega, D. et al. Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment. PLoS ONE 4, e7819 (2009).

    PubMed  PubMed Central  Google Scholar 

  25. Fagone, P. & Jackowski, S. Phosphatidylcholine and the CDP–choline cycle. Biochim. Biophys. Acta 1831, 523–532 (2013).

    CAS  PubMed  Google Scholar 

  26. Chen, W. W., Freinkman, E., Wang, T., Birsoy, K. & Sabatini, D. M. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166, 1324–1337 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

  28. Wu, G., Aoyama, C., Young, S. G. & Vance, D. E. Early embryonic lethality caused by disruption of the gene for choline kinase α, the first enzyme in phosphatidylcholine biosynthesis. J. Biol. Chem. 283, 1456–1462 (2008).

    CAS  PubMed  Google Scholar 

  29. Haider, A. et al. PCYT1A regulates phosphatidylcholine homeostasis from the inner nuclear membrane in response to membrane stored curvature elastic stress. Dev. Cell 45, 481–495 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Krahmer, N. et al. Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine cytidylyltransferase. Cell Metab. 14, 504–515 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, L., Magdaleno, S., Tabas, I. & Jackowski, S. Early embryonic lethality in mice with targeted deletion of the CTP:phosphocholine cytidylyltransferase α gene (Pcyt1a). Mol. Cell. Biol. 25, 3357–3363 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lykidis, A., Baburina, I. & Jackowski, S. Distribution of CTP:phosphocholine cytidylyltransferase (CCT) isoforms. J. Biol. Chem. 274, 26992–27001 (1999).

    CAS  PubMed  Google Scholar 

  33. Henneberry, A. L. & McMaster, C. R. Cloning and expression of a human choline/ethanolaminephosphotransferase: synthesis of phosphatidylcholine and phosphatidylethanolamine. Biochem. J. 339, 291–298 (1999).

    PubMed  PubMed Central  Google Scholar 

  34. Henneberry, A. L., Wistow, G. & McMaster, C. R. Cloning, genomic organization, and characterization of a human cholinephosphotransferase. J. Biol. Chem. 275, 29808–29815 (2000).

    CAS  PubMed  Google Scholar 

  35. Wang, Z., Yang, M., Yang, Y., He, Y. & Qian, H. Structural basis for catalysis of human choline/ethanolamine phosphotransferase 1. Nat. Commun. 14, 2529 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, L. & Zhou, M. Structure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis. Nat. Commun. 14, 2753 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mödinger, Y., Schön, C., Wilhelm, M. & Hals, P. A. Plasma kinetics of choline and choline metabolites after a single dose of SuperbaBoost krill oil or choline bitartrate in healthy volunteers. Nutrients 11, 2548 (2019).

    PubMed  PubMed Central  Google Scholar 

  38. Garguilo, M. G. & Michael, A. C. Amperometric microsensors for monitoring choline in the extracellular fluid of brain. J. Neurosci. Methods 70, 73–82 (1996).

    CAS  PubMed  Google Scholar 

  39. Brehm, R., Lindmar, R. & Löffelholz, K. Muscarinic mobilization of choline in rat brain in vivo as shown by the cerebral arterio‐venous difference of choline. J. Neurochem. 48, 1480–1485 (1987).

    CAS  PubMed  Google Scholar 

  40. Bianchi, L. et al. Extracellular levels of amino acids and choline in human high grade gliomas: an intraoperative microdialysis study. Neurochem. Res. 29, 325–334 (2004).

  41. Mulder, A. H., Yamamura, H. I., Kuhar, M. J. & Snyder, S. H. Release of acetylcholine from hippocampal slices by potassium depolarization: dependence on high affinity choline uptake. Brain Res. 70, 372–376 (1974).

    CAS  PubMed  Google Scholar 

  42. Perry, W. L. M. Acetylcholine release in the cat’s superior cervical ganglion. J. Physiol. 119, 439–454 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ennis, E. A. & Blakely, R. D. Choline on the move: perspectives on the molecular physiology and pharmacology of the presynaptic choline transporter. Adv. Pharm. 76, 175–213 (2016).

    CAS  Google Scholar 

  44. Hodgkin, A. L. & Martin, K. Choline uptake by giant axons of Loligo. J. Physiol. 179, 26P–27P (1965).

    CAS  Google Scholar 

  45. Martin, K. Concentrative accumulation of choline by human erythrocytes. J. Gen. Physiol. 51, 497–516 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Okuda, T. et al. Identification and characterization of the high-affinity choline transporter. Nat. Neurosci. 3, 120–125 (2000).

    CAS  PubMed  Google Scholar 

  47. Apparsundaram, S., Ferguson, S. M., George, A. L. & Blakely, R. D. Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem. Biophys. Res. Commun. 276, 862–867 (2000).

    CAS  PubMed  Google Scholar 

  48. Apparsundaram, S., Ferguson, S. M. & Blakely, R. D. Molecular cloning and characterization of a murine hemicholinium-3-sensitive choline transporter. Biochem. Soc. Trans. 29, 711–716 (2001).

    CAS  PubMed  Google Scholar 

  49. Inazu, M. Functional expression of choline transporters in the blood–brain barrier. Nutrients 10.3390/nu11102265 (2019).

  50. Qiu, Y., Gao, Y., Huang, B., Bai, Q. & Zhao, Y. Transport mechanism of presynaptic high-affinity choline uptake by CHT1. Nat. Struct. Mol. Biol. 31, 701–709 (2024).

    CAS  PubMed  Google Scholar 

  51. Ferguson, S. M. et al. Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. J. Neurosci. 23, 9697–9709 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Nakata, K., Okuda, T. & Misawa, H. Ultrastructural localization of high‐affinity choline transporter in the rat neuromuscular junction: enrichment on synaptic vesicles. Synapse 53, 53–56 (2004).

  53. Holmstrand, E. C., Asafu‐Adjei, J., Sampson, A. R., Blakely, R. D. & Sesack, S. R. Ultrastructural localization of high‐affinity choline transporter in the rat anteroventral thalamus and ventral tegmental area: differences in axon morphology and transporter distribution. J. Comp. Neurol. 518, 1908–1924 (2010).

    PubMed  PubMed Central  Google Scholar 

  54. Ferguson, S. M. et al. Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice. Proc. Natl Acad. Sci. USA 101, 8762–8767 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. O’Regan, S. et al. An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins. Proc. Natl Acad. Sci. USA 97, 1835–1840 (2000).

    PubMed  PubMed Central  Google Scholar 

  56. Yuan, Z., Wagner, L., Poloumienko, A. & Bakovic, M. Identification and expression of a mouse muscle-specific CTL1 gene. Gene 341, 305–312 (2004).

    CAS  PubMed  Google Scholar 

  57. Wille, S. et al. Characterization of CDw92 as a member of the choline transporter-like protein family regulated specifically on dendritic cells. J. Immunol. 167, 5795–5804 (2001).

    CAS  PubMed  Google Scholar 

  58. Fullerton, M. D., Wagner, L., Yuan, Z. & Bakovic, M. Impaired trafficking of choline transporter-like protein-1 at plasma membrane and inhibition of choline transport in THP-1 monocyte-derived macrophages. Am. J. Physiol. Cell Physiol. 290, C1230–C1238 (2006).

    CAS  PubMed  Google Scholar 

  59. Inazu, M., Takeda, H. & Matsumiya, T. Molecular and functional characterization of an Na+-independent choline transporter in rat astrocytes. J. Neurochem. 94, 1427–1437 (2005).

    CAS  PubMed  Google Scholar 

  60. Fagerberg, C. R. et al. Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration. Brain 143, 94–111 (2020).

    PubMed  Google Scholar 

  61. Sanchez-Lopez, E. et al. Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production. Cell Metab. 29, 1350–1362 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Snider, S. A. et al. Choline transport links macrophage phospholipid metabolism and inflammation. J. Biol. Chem. 293, 11600–11611 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Inazu, M. Choline transporter-like proteins CTLs/SLC44 family as a novel molecular target for cancer therapy. Biopharm. Drug Dispos. 35, 431–449 (2014).

    CAS  PubMed  Google Scholar 

  64. Hedtke, V. & Bakovic, M. Choline transport for phospholipid synthesis: an emerging role of choline transporter-like protein 1. Exp. Biol. Med 244, 655–662 (2019).

    CAS  Google Scholar 

  65. Michel, V., Yuan, Z., Ramsubir, S. & Bakovic, M. Choline transport for phospholipid synthesis. Exp. Biol. Med. 231, 490–504 (2006).

    CAS  Google Scholar 

  66. Michel, V. & Bakovic, M. The solute carrier 44A1 is a mitochondrial protein and mediates choline transport. FASEB J. 23, 2749–2758 (2009).

    CAS  PubMed  Google Scholar 

  67. Taylor, A., Grapentine, S., Ichhpuniani, J. & Bakovic, M. Choline transporter-like proteins 1 and 2 are newly identified plasma membrane and mitochondrial ethanolamine transporters. J. Biol. Chem. 296, 100604 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Nakata, T., Matsui, T., Kobayashi, K., Kobayashi, Y. & Anzai, N. Organic cation transporter 2 (SLC22A2), a low-affinity and high-capacity choline transporter, is preferentially enriched on synaptic vesicles in cholinergic neurons. Neuroscience 252, 212–221 (2013).

    CAS  PubMed  Google Scholar 

  69. Sinclair, C. J., Chi, K. D., Subramanian, V., Ward, K. L. & Green, R. M. Functional expression of a high affinity mammalian hepatic choline/organic cation transporter. J. Lipid Res. 41, 1841–1848 (2000).

    CAS  PubMed  Google Scholar 

  70. Kenny, T. C. et al. Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals. Cell Metab. 35, 1057–1071 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Quigley, J. G. et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell 118, 757–766 (2004).

    CAS  PubMed  Google Scholar 

  72. Keel, S. B. et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319, 825–828 (2008).

    CAS  PubMed  Google Scholar 

  73. Fiorito, V. & Tolosano, E. Unearthing FLVCR1a: tracing the path to a vital cellular transporter. Cell. Mol. Life Sci. 81, 166 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, Q. et al. Metagenomic and metabolomic remodeling in nonagenarians and centenarians and its association with genetic and socioeconomic factors. Nat. Aging 2, 438–452 (2022).

    CAS  PubMed  Google Scholar 

  75. Moore, A. et al. Genome-wide metabolite quantitative trait loci analysis (mQTL) in red blood cells from volunteer blood donors. J. Biol. Chem. 298, 102706–102707 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tsuchiya, M., Tachibana, N., Nagao, K., Tamura, T. & Hamachi, I. Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism. Cell Metab. 35, 1072–1083 (2023).

  77. Scharenberg, S. G. et al. An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation. Sci. Adv. 9, eadf8966 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. He, M. et al. Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage. Proc. Natl Acad. Sci. USA 119, e2210353119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ha, H. T. et al. Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models. JCI Insight 9, e175462 (2024).

    PubMed  PubMed Central  Google Scholar 

  80. Rajadhyaksha, A. M. et al. Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am. J. Hum. Genet. 87, 643–654 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Yanatori, I., Yasui, Y., Miura, K. & Kishi, F. Mutations of FLVCR1 in posterior column ataxia and retinitis pigmentosa result in the loss of heme export activity. Blood Cells Mol. Dis. 49, 60–66 (2012).

    CAS  PubMed  Google Scholar 

  82. Vaughan, D. P., Costello, D. J. & David Vaughan, C. P. Extending the phenotype of posterior column ataxia with retinitis pigmentosa caused by variants in FLVCR1. Am. J. Med. Genet. A https://doi.org/10.1002/AJMG.A.62612 (2021).

    Article  PubMed  Google Scholar 

  83. Calame, D. G. et al. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum. Genet. Med. https://doi.org/10.1016/J.GIM.2024.101273 (2024).

  84. Grudzinska Pechhacker, M. K. et al. FLVCR1-related disease as a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy. Eur. J. Med. Genet. 63, 104037 (2020).

    PubMed  Google Scholar 

  85. Kuk, A. C. Y. & Silver, D. L. The cellular supply-side economics for phospholipids. Cell Metab. 35, 909–911 (2023).

    CAS  PubMed  Google Scholar 

  86. Ha, H. T. T. et al. Mfsd7b facilitates choline transport and missense mutations affect choline transport function. Cell. Mol. Life Sci. 81, 3 (2024).

    CAS  Google Scholar 

  87. Nguyen, X. T. A. et al. MFSD7c functions as a transporter of choline at the blood–brain barrier. Cell Res. 34, 245–257 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kalailingam, P. et al. Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome. J. Clin. Invest. 130, 4081–4093 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Cater, R. J. et al. Structural and molecular basis of choline uptake into the brain by FLVCR2. Nature 629, 704–709 (2024).

    CAS  PubMed  Google Scholar 

  90. Son, Y., Kenny, T. C., Khan, A., Birsoy, K. & Hite, R. K. Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1. Nature https://doi.org/10.1038/s41586-024-07374-4 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ri, K. et al. Molecular mechanism of choline and ethanolamine transport in humans. Nature 630, 501–508 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Nguyen, L. N. et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509, 503–506 (2014).

    CAS  PubMed  Google Scholar 

  93. Wong, B. H. et al. Mfsd2a is a transporter for the essential ω-3 fatty acid docosahexaenoic acid (DHA) in eye and is important for photoreceptor cell development. J. Biol. Chem. 291, 10501–10514 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Chua, G. -L. et al. Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport. Proc. Natl Acad. Sci. USA 120, e2215290120 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Walter, J. D., Remm, S. & Seeger, M. A. Fatty acid transporter MFSD2A is a multifunctional gatekeeper in brain and placenta. Nat. Struct. Mol. Biol. 29, 504–506 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wood, C. A. P. et al. Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A. Nature 596, 444–448 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Quek, D. Q. Y., Nguyen, L. N., Fan, H. & Silver, D. L. Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter MFSD2A. J. Biol. Chem. 291, 9383–9394 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Cater, R. J. et al. Structural basis of omega-3 fatty acid transport across the blood–brain barrier. Nature 595, 315–319 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Harel, T. et al. Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination. Neurogenetics 19, 227–235 (2018).

    PubMed  Google Scholar 

  100. Guemez-Gamboa, A. et al. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat. Genet. 47, 809–813 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Alakbarzade, V. et al. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat. Genet. 47, 814–817 (2015).

    CAS  PubMed  Google Scholar 

  102. Scala, M. et al. Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features. Eur. J. Hum. Genet. 28, 1509–1519 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhou, J. et al. Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis. Sci. Adv. 5, eaax7142 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Abe, A., Kelly, R. & Shayman, J. A. The measurement of lysosomal phospholipase A2 activity in plasma. J. Lipid Res. 51, 2464–2470 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hiraoka, M., Abe, A. & Shayman, J. A. Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase. J. Biol. Chem. 277, 10090–10099 (2002).

    CAS  PubMed  Google Scholar 

  106. Hinkovska-Galcheva, V. et al. Determinants of pH profile and acyl chain selectivity in lysosomal phospholipase A2. J. Lipid Res. 59, 1205–1218 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Glukhova, A. et al. Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase. Nat. Commun. 6, 6250 (2015).

    CAS  PubMed  Google Scholar 

  108. Hiraoka, M. et al. Lysosomal phospholipase A2 and phospholipidosis. Mol. Cell. Biol. 26, 6139–6148 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Hostetler, K. Y., Yazaki, P. J. & van den Bosch, H. Purification of lysosomal phospholipase A. Evidence for multiple isoenzymes in rat liver. J. Biol. Chem. 257, 13367–13373 (1982).

    CAS  PubMed  Google Scholar 

  110. Franson, R., Waite, M. & LaVia, M. Identification of phospholipase A1 and A2 in the soluble fraction of rat liver lysosomes. Biochemistry 10, 1942–1946 (1971).

    CAS  PubMed  Google Scholar 

  111. Nyame, K. et al. PLA2G15 is a lysosomal BMP hydrolase with ester position specificity and its targeting ameliorates lysosomal disease. Preprint at bioRxiv https://doi.org/10.1101/2024.06.07.597919 (2024).

  112. Kretzschmar, D. PNPLA6/NTE, an evolutionary conserved phospholipase linked to a group of complex human diseases. Metabolites 12, 284 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Van Tienhoven, M., Atkins, J., Li, Y. & Glynn, P. Human neuropathy target esterase catalyzes hydrolysis of membrane lipids. J. Biol. Chem. 277, 20942–20948 (2002).

    PubMed  Google Scholar 

  114. Lush, M. J., Li, Y., Read, D. J., Willis, A. C. & Glynn, P. Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man. Biochem. J. 332, 1–4 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Glynn, P. Neuronal phospholipid deacylation is essential for axonal and synaptic integrity. Biochim. Biophys. Acta 1831, 633–641 (2013).

    CAS  PubMed  Google Scholar 

  116. Nyame, K. et al. Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease. Mol. Cell 84, 1354–1364 (2024).

  117. Laqtom, N. N. et al. CLN3 is required for the clearance of glycerophosphodiesters from lysosomes. Nature 609, 1005–1011 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ridgway, N. D. & Vance, D. E. Purification of phosphatidylethanolamine N-methyltransferase from rat liver. J. Biol. Chem. 262, 17231–17239 (1987).

    CAS  PubMed  Google Scholar 

  119. Huitema, K., van den Dikkenberg, J., Brouwers, J. F. H. M. & Holthuis, J. C. M. Identification of a family of animal sphingomyelin synthases. EMBO J. 23, 33–44 (2004).

    CAS  PubMed  Google Scholar 

  120. Tafesse, F. G. et al. Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells. J. Biol. Chem. 282, 17537–17547 (2007).

    CAS  PubMed  Google Scholar 

  121. Okazaki, Y. et al. A novel glycerophosphodiester phosphodiesterase, GDE5, controls skeletal muscle development via a non-enzymatic mechanism. J. Biol. Chem. 285, 27652–27663 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Gallazzini, M., Ferraris, J. D. & Burg, M. B. GDPD5 is a glycerophosphocholine phosphodiesterase that osmotically regulates the osmoprotective organic osmolyte GPC. Proc. Natl Acad. Sci. USA 105, 11026–11031 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hammond, S. M. et al. Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. J. Biol. Chem. 270, 29640–29643 (1995).

    CAS  PubMed  Google Scholar 

  124. Lopez, I., Arnold, R. S. & Lambeth, J. D. Cloning and initial characterization of a human phospholipase D2 (hPLD2). ADP-ribosylation factor regulates hPLD2. J. Biol. Chem. 273, 12846–12852 (1998).

    CAS  PubMed  Google Scholar 

  125. Saito de, R. F., Andrade de, L. N. S., Bustos, S. O. & Chammas, R. Phosphatidylcholine-derived lipid mediators: the crosstalk between cancer cells and immune cells. Front. Immunol. 13, 768606 (2022).

    Google Scholar 

  126. Blusztajn, J. K., Lopez Gonzalez-Coviella, I., Logue, M., Growdon, J. H. & Wurtman, R. J. Levels of phospholipid catabolic intermediates, glycerophosphocholine and glycerophosphoethanolamine, are elevated in brains of Alzheimer’s disease but not of Down’s syndrome patients. Brain Res. 536, 240–244 (1990).

    CAS  PubMed  Google Scholar 

  127. Pahud, G. et al. Study of subcellular localization of membrane-bound choline acetyltransferase in Drosophila central nervous system and its association with membranes. Eur. J. Neurosci. 10, 1644–1653 (1998).

    CAS  PubMed  Google Scholar 

  128. Tandon, A., Bachoo, M., Weldon, P., Polosa, C. & Collier, B. Effects of colchicine application to preganglionic axons on choline acetyltransferase activity and acetylcholine content and release in the superior cervical ganglion. J. Neurochem. 66, 1033–1041 (1996).

    CAS  PubMed  Google Scholar 

  129. Lever, M. & Slow, S. The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin. Biochem. 43, 732–744 (2010).

    CAS  PubMed  Google Scholar 

  130. Craig, S. A. Betaine in human nutrition. Am. J. Clin. Nutr. 80, 539–549 (2004).

    CAS  PubMed  Google Scholar 

  131. Alvarenga, L., Ferreira, M. S., Kemp, J. A. & Mafra, D. The role of betaine in patients with chronic kidney disease: a narrative review. Curr. Nutr. Rep. 11, 395–406 (2022).

    CAS  PubMed  Google Scholar 

  132. Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2017).

    CAS  PubMed  Google Scholar 

  133. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Baker, J. R. & Chaykin, S. The biosynthesis of trimethylamine-N-oxide. J. Biol. Chem. 237, 1309–1313 (1962).

    CAS  PubMed  Google Scholar 

  135. Wang, H. et al. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab. 34, 581–594 (2022).

    CAS  PubMed  Google Scholar 

  136. Chen, S. et al. Trimethylamine N-oxide binds and activates PERK to promote metabolic dysfunction. Cell Metab. 30, 1141–1151 (2019).

    CAS  PubMed  Google Scholar 

  137. Yoo, W. et al. High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine N-oxide. Science 373, 813–818 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Vance, J. E. Phospholipid synthesis and transport in mammalian cells. Traffic 16, 1–18 (2015).

    CAS  PubMed  Google Scholar 

  139. van Meer, G., Voelker, D. R. & Feigenson, G. W. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9, 112–124 (2008).

    PubMed  PubMed Central  Google Scholar 

  140. Horibata, Y. & Sugimoto, H. StarD7 mediates the intracellular trafficking of phosphatidylcholine to mitochondria. J. Biol. Chem. 285, 7358–7365 (2010).

    CAS  PubMed  Google Scholar 

  141. Khan, A. et al. Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import. Nat. Genet. 56, 1614–1623 (2024).

    CAS  PubMed  Google Scholar 

  142. Schlosser, P. et al. Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine. Nat. Genet. 55, 995–1008 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Patil, S. et al. The membrane transporter SLC25A48 enables transport of choline into human mitochondria. Kidney Int. https://doi.org/10.1016/j.kint.2024.06.022 (2024).

  144. Verkerke, A. R. P. et al. SLC25A48 controls mitochondrial choline import and metabolism. Cell Metab. 36, 2156–2166 (2024).

  145. Hollenbeck, C. B. An introduction to the nutrition and metabolism of choline. Cent. Nerv. Syst. Agents Med. Chem. 12, 100–113 (2012).

    CAS  PubMed  Google Scholar 

  146. Li, J., Xin, Y., Li, J., Chen, H. & Li, H. Phosphatidylethanolamine N-methyltransferase: from functions to diseases. Aging Dis. 14, 879–891 (2023).

    PubMed  PubMed Central  Google Scholar 

  147. Zeisel, S. H. & da Costa, K. -A. Choline: an essential nutrient for public health. Nutr. Rev. 67, 615–623 (2009).

    PubMed  Google Scholar 

  148. Wallace, T. C. et al. Choline: the underconsumed and underappreciated essential nutrient. Nutr. Today 53, 240–253 (2018).

    PubMed  PubMed Central  Google Scholar 

  149. Sanders, L. M. & Zeisel, S. H. Choline: dietary requirements and role in brain development. Nutr. Today 42, 181–186 (2007).

    PubMed  PubMed Central  Google Scholar 

  150. Leermakers, E. T. et al. Effects of choline on health across the life course: a systematic review. Nutr. Rev. 73, 500–522 (2015).

    PubMed  Google Scholar 

  151. Wiedeman, A. M. et al. Dietary choline intake: current state of knowledge across the life cycle. Nutrients 10, 1513 (2018).

    PubMed  PubMed Central  Google Scholar 

  152. Zeisel, S. H. Dietary choline: biochemistry, physiology, and pharmacology. Annu. Rev. Nutr. 1, 95–121 (1981).

    CAS  PubMed  Google Scholar 

  153. Zeisel, S. H., Growdon, J. H., Wurtman, R. J., Magil, S. G. & Logue, M. Normal plasma choline responses to ingested lecithin. Neurology 30, 1226–1229 (1980).

    CAS  PubMed  Google Scholar 

  154. Horie, A., Ishida, K., Watanabe, Y., Shibata, K. & Hashimoto, Y. Membrane transport mechanisms of choline in human intestinal epithelial LS180 cells. Biopharm. Drug Dispos. 35, 532–542 (2014).

    CAS  PubMed  Google Scholar 

  155. Lee, N. Y., Choi, H. M. & Kang, Y. S. Choline transport via choline transporter-like protein 1 in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBT. Placenta 30, 368–374 (2009).

    CAS  PubMed  Google Scholar 

  156. Zeisel, S. H. Choline: critical role during fetal development and dietary requirements in adults. Annu. Rev. Nutr. 26, 229–250 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ensminger, M. E., Bowland, J. P. & Cunha, T. J. Observations on the thiamine, riboflavin, and choline needs of sows for reproduction. J. Anim. Sci. 6, 409–423 (1947).

    CAS  PubMed  Google Scholar 

  158. Meader, R. D. Livers of choline-deficient pregnant and fetal rats. Anat. Rec. 153, 407–419 (1965).

    CAS  PubMed  Google Scholar 

  159. da Costa, K. A. et al. Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J. 20, 1336–1344 (2006).

    PubMed  Google Scholar 

  160. Kohlmeier, M., da Costa, K. A., Fischer, L. M. & Zeisel, S. H. Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. Proc. Natl Acad. Sci. USA 102, 16025–16030 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Vance, D. E. & Vance, J. E. Physiological consequences of disruption of mammalian phospholipid biosynthetic genes. J. Lipid Res. 50, S132–S137 (2009).

    PubMed  PubMed Central  Google Scholar 

  162. Brody, L. C. et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am. J. Hum. Genet. 71, 1207–1215 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Jacob, R. A., Jenden, D. J., Allman-Farinelli, M. A. & Swendseid, M. E. Folate nutriture alters choline status of women and men fed low choline diets. J. Nutr. 129, 712–717 (1999).

    CAS  PubMed  Google Scholar 

  164. Kim, Y. I. et al. Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. J. Nutr. 124, 2197–2203 (1994).

    CAS  PubMed  Google Scholar 

  165. Ananth, M. R., Rajebhosale, P., Kim, R., Talmage, D. A. & Role, L. W. Basal forebrain cholinergic signalling: development, connectivity and roles in cognition. Nat. Rev. Neurosci. 24, 233–251 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Picciotto, M. R., Higley, M. J. & Mineur, Y. S. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76, 116–129 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Carlson, A. B. & Kraus, G. P. Physiology, Cholinergic Receptors (StatPearls Publishing, 2024).

  168. Giocomo, L. M. & Hasselmo, M. E. Neuromodulation by glutamate and acetylcholine can change circuit dynamics by regulating the relative influence of afferent input and excitatory feedback. Mol. Neurobiol. 36, 184–200 (2007).

    CAS  PubMed  Google Scholar 

  169. McKay, B. E., Placzek, A. N. & Dani, J. A. Regulation of synaptic transmission and plasticity by neuronal nicotinic acetylcholine receptors. Biochem. Pharmacol. 74, 1120–1133 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Yao, Z. M. & Vance, D. E. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J. Biol. Chem. 263, 2998–3004 (1988).

    CAS  PubMed  Google Scholar 

  171. Cole, L. K., Vance, J. E. & Vance, D. E. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim. Biophys. Acta 1821, 754–761 (2012).

    CAS  PubMed  Google Scholar 

  172. Kansakar, U. et al. Choline supplements: an update. Front. Endocrinol. 14, 1148166 (2023).

    Google Scholar 

  173. Barrios, J. M. & Lichtenberger, L. M. Role of biliary phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats. Gastroenterology 118, 1179–1186 (2000).

    CAS  PubMed  Google Scholar 

  174. Boyer, J. L. Bile formation and secretion. Compr. Physiol. 3, 1035–1078 (2013).

    PubMed  PubMed Central  Google Scholar 

  175. Small, D. M. Role of ABC transporters in secretion of cholesterol from liver into bile. Proc. Natl Acad. Sci. USA 100, 4–6 (2003).

    CAS  PubMed  Google Scholar 

  176. Li, Z., Agellon, L. B. & Vance, D. E. Phosphatidylcholine homeostasis and liver failure. J. Biol. Chem. 280, 37798–37802 (2005).

    CAS  PubMed  Google Scholar 

  177. Phang-Lyn, S. & Llerena, V. A. Biochemistry, Biotransformation (StatPearls Publishing, 2024).

  178. Goss, V., Hunt, A. N. & Postle, A. D. Regulation of lung surfactant phospholipid synthesis and metabolism. Biochim. Biophys. Acta 1831, 448–458 (2013).

    CAS  PubMed  Google Scholar 

  179. Bernhard, W. et al. Phosphatidylcholine molecular species in lung surfactant: composition in relation to respiratory rate and lung development. Am. J. Respir. Cell Mol. Biol. 25, 725–731 (2001).

    CAS  PubMed  Google Scholar 

  180. Hamm, H., Fabel, H. & Bartsch, W. The surfactant system of the adult lung: physiology and clinical perspectives. Clin. Investig. 70, 637–657 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Nakanishi, T., Turner, R. J. & Burg, M. B. Osmoregulation of betaine transport in mammalian renal medullary cells. Am. J. Physiol. 258, F1061–F1067 (1990).

    CAS  PubMed  Google Scholar 

  182. Bagnasco, S., Balaban, R., Fales, H. M., Yang, Y. M. & Burg, M. Predominant osmotically active organic solutes in rat and rabbit renal medullas. J. Biol. Chem. 261, 5872–5877 (1986).

    CAS  PubMed  Google Scholar 

  183. Kempson, S. A., Vovor-Dassu, K. & Day, C. Betaine transport in kidney and liver: use of betaine in liver injury. Cell. Physiol. Biochem. 32, 32–40 (2013).

    CAS  PubMed  Google Scholar 

  184. Kempson, S. A., Zhou, Y. & Danbolt, N. C. The betaine/GABA transporter and betaine: roles in brain, kidney, and liver. Front Physiol. 5, 159 (2014).

    PubMed  PubMed Central  Google Scholar 

  185. Huang, Y. H., Schafer-Elinder, L., Wu, R., Claesson, H. E. & Frostegard, J. Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. Clin. Exp. Immunol. 116, 326–331 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Carneiro, A. B. et al. Lysophosphatidylcholine triggers TLR2- and TLR4-mediated signaling pathways but counteracts LPS-induced NO synthesis in peritoneal macrophages by inhibiting NF-κB translocation and MAPK/ERK phosphorylation. PLoS ONE 8, e76233 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Ashraf, M. A. & Nookala, V. Biochemistry of Platelet Activating Factor (StatPearls Publishing, 2024).

  188. Billipp, T. E. et al. Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance. Immunity 57, 1243–1259 (2024).

    CAS  PubMed  Google Scholar 

  189. Ndjim, M. et al. Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity. Immunity 57, 1260–1273 (2024).

    CAS  PubMed  Google Scholar 

  190. Wiedeman, A. M. et al. Concentrations of water-soluble forms of choline in human milk from lactating women in Canada and Cambodia. Nutrients 10, 381 (2018).

    PubMed  PubMed Central  Google Scholar 

  191. Zeisel, S. H., Epstein, M. F. & Wurtman, R. J. Elevated choline concentration in neonatal plasma. Life Sci. 26, 1827–1831 (1980).

    CAS  PubMed  Google Scholar 

  192. Buchman, A. L. et al. Plasma choline in normal newborns, infants, toddlers, and in very-low-birth-weight neonates requiring total parenteral nutrition. Nutrition 17, 18–21 (2001).

    CAS  PubMed  Google Scholar 

  193. Bragg, M. G., Prado, E. L. & Stewart, C. P. Choline and docosahexaenoic acid during the first 1000 days and children’s health and development in low- and middle-income countries. Nutr. Rev. 80, 656–676 (2022).

    PubMed  Google Scholar 

  194. Albright, C. D., Tsai, A. Y., Friedrich, C. B., Mar, M. H. & Zeisel, S. H. Choline availability alters embryonic development of the hippocampus and septum in the rat. Brain Res. Dev. Brain Res. 113, 13–20 (1999).

    CAS  PubMed  Google Scholar 

  195. Albright, C. D., Friedrich, C. B., Brown, E. C., Mar, M. H. & Zeisel, S. H. Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum. Brain Res. Dev. Brain Res. 115, 123–129 (1999).

    CAS  PubMed  Google Scholar 

  196. Pyapali, G. K., Turner, D. A., Williams, C. L., Meck, W. H. & Swartzwelder, H. S. Prenatal dietary choline supplementation decreases the threshold for induction of long-term potentiation in young adult rats. J. Neurophysiol. 79, 1790–1796 (1998).

    CAS  PubMed  Google Scholar 

  197. Niculescu, M. D., Craciunescu, C. N. & Zeisel, S. H. Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J. 20, 43–49 (2006).

    CAS  PubMed  Google Scholar 

  198. Fisher, M. C., Zeisel, S. H., Mar, M. H. & Sadler, T. W. Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro. FASEB J. 16, 619–621 (2002).

    CAS  PubMed  Google Scholar 

  199. Lauder, J. M. & Schambra, U. B. Morphogenetic roles of acetylcholine. Environ. Health Perspect. 107, 65–69 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Li, Q. et al. Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J. Neurophysiol. 91, 1545–1555 (2004).

    CAS  PubMed  Google Scholar 

  201. Williams, C. L., Meck, W. H., Heyer, D. D. & Loy, R. Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats. Brain Res. 794, 225–238 (1998).

    CAS  PubMed  Google Scholar 

  202. Jones, J. P., Meck, W. H., Williams, C. L., Wilson, W. A. & Swartzwelder, H. S. Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation. Brain Res. Dev. Brain Res. 118, 159–167 (1999).

    CAS  PubMed  Google Scholar 

  203. Meck, W. H. & Williams, C. L. Characterization of the facilitative effects of perinatal choline supplementation on timing and temporal memory. Neuroreport 8, 2831–2835 (1997).

    CAS  PubMed  Google Scholar 

  204. Meck, W. H. & Williams, C. L. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci. Biobehav. Rev. 27, 385–399 (2003).

    CAS  PubMed  Google Scholar 

  205. Meck, W. H. & Williams, C. L. Perinatal choline supplementation increases the threshold for chunking in spatial memory. Neuroreport 8, 3053–3059 (1997).

    CAS  PubMed  Google Scholar 

  206. Meck, W. H. & Williams, C. L. Simultaneous temporal processing is sensitive to prenatal choline availability in mature and aged rats. Neuroreport 8, 3045–3051 (1997).

    CAS  PubMed  Google Scholar 

  207. Meck, W. H., Smith, R. A. & Williams, C. L. Pre- and postnatal choline supplementation produces long-term facilitation of spatial memory. Dev. Psychobiol. 21, 339–353 (1988).

    CAS  PubMed  Google Scholar 

  208. Wortmann, S. B. & Mayr, J. A. Choline-related-inherited metabolic diseases—a mini review. J. Inherit. Metab. Dis. 42, 237–242 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Mitsuhashi, S. et al. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am. J. Hum. Genet. 88, 845–851 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Barwick, K. E. et al. Defective presynaptic choline transport underlies hereditary motor neuropathy. Am. J. Hum. Genet. 91, 1103–1107 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Ohno, K. et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc. Natl Acad. Sci. USA 98, 2017–2022 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Hoover-Fong, J. et al. Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am. J. Hum. Genet. 94, 105–112 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Yamamoto, G. L. et al. Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am. J. Hum. Genet. 94, 113–119 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Payne, F. et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc. Natl Acad. Sci. USA 111, 8901–8906 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Zeisel, S. H. et al. Choline deficiency selects for resistance to p53-independent apoptosis and causes tumorigenic transformation of rat hepatocytes. Carcinogenesis 18, 731–738 (1997).

    CAS  PubMed  Google Scholar 

  216. Sha, W. et al. Metabolomic profiling can predict which humans will develop liver dysfunction when deprived of dietary choline. FASEB J. 24, 2962–2975 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Corbin, K. D. & Zeisel, S. H. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr. Opin. Gastroenterol. 28, 159–165 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Li, Z., Agellon, L. B. & Vance, D. E. Choline redistribution during adaptation to choline deprivation. J. Biol. Chem. 282, 10283–10289 (2007).

    CAS  PubMed  Google Scholar 

  219. Corbin, K. D. et al. Genetic signatures in choline and 1-carbon metabolism are associated with the severity of hepatic steatosis. FASEB J. 27, 1674–1689 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Mehedint, M. G. & Zeisel, S. H. Choline’s role in maintaining liver function: new evidence for epigenetic mechanisms. Curr. Opin. Clin. Nutr. Metab. Care 16, 339–345 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Hensley, K. et al. Dietary choline restriction causes complex I dysfunction and increased H2O2 generation in liver mitochondria. Carcinogenesis 21, 983–989 (2000).

    CAS  PubMed  Google Scholar 

  222. Zhan, X. et al. Choline supplementation regulates gut microbiome diversity, gut epithelial activity, and the cytokine gene expression in gilts. Front. Nutr. 10, 1101519 (2023).

    PubMed  PubMed Central  Google Scholar 

  223. Glunde, K., Jacobs, M. A. & Bhujwalla, Z. M. Choline metabolism in cancer: implications for diagnosis and therapy. Expert Rev. Mol. Diagn. 6, 821–829 (2006).

    CAS  PubMed  Google Scholar 

  224. Glunde, K., Bhujwalla, Z. M. & Ronen, S. M. Choline metabolism in malignant transformation. Nat. Rev. Cancer 11, 835–848 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Lee, Z. [18F]-choline PET/CT as an imaging biomarker for primary liver cancers. Transl. Cancer Res. 5, S1489–S1492 (2016).

    PubMed  Google Scholar 

  226. Murphy, R. C., Kawashima, A. & Peller, P. J. The utility of 11C-choline PET/CT for imaging prostate cancer: a pictorial guide. AJR Am. J. Roentgenol. 196, 1390–1398 (2011).

    PubMed  Google Scholar 

  227. Guo, Y., Wang, L., Hu, J., Feng, D. & Xu, L. Diagnostic performance of choline PET/CT for the detection of bone metastasis in prostate cancer: a systematic review and meta-analysis. PLoS ONE 13, e0203400 (2018).

    PubMed  PubMed Central  Google Scholar 

  228. Zhang, R. R. et al. Next-generation cancer magnetic resonance imaging with tumor-targeted alkylphosphocholine metal analogs. Invest. Radio. 57, 655–663 (2022).

    CAS  Google Scholar 

  229. Weichert, J. P. et al. Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy. Sci. Transl. Med. 6, 240ra75 (2014).

    PubMed  PubMed Central  Google Scholar 

  230. Yuan, J. et al. Is dietary choline intake related to dementia and Alzheimer’s disease risks? Results from the Framingham Heart Study. Am. J. Clin. Nutr. 116, 1201–1207 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Chen, Z. R., Huang, J. B., Yang, S. L. & Hong, F. F. Role of cholinergic signaling in Alzheimer’s disease. Molecules 27, 1816 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Bertrand, D. & Wallace, T. L. A review of the cholinergic system and therapeutic approaches to treat brain disorders. Curr. Top. Behav. Neurosci. 45, 1–28 (2020).

    CAS  PubMed  Google Scholar 

  233. Dave, N. et al. Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimer’s disease hallmarks. Aging Cell 22, e13775 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Velazquez, R. et al. Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation. Aging Cell 18, e13037 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Pepeu, G. & Grazia Giovannini, M. The fate of the brain cholinergic neurons in neurodegenerative diseases. Brain Res. 1670, 173–184 (2017).

    CAS  PubMed  Google Scholar 

  236. Lorent, J. H. et al. Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape. Nat. Chem. Biol. 16, 644–652 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Li, Z. et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 3, 321–331 (2006).

    CAS  PubMed  Google Scholar 

  238. Ma, D. W. L. et al. Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects. Nutr. Diabetes 6, e220–e220 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Cornell, R. & Antonny, B. CCTα commands phospholipid homeostasis from the nucleus. Dev. Cell 45, 419–420 (2018).

    CAS  PubMed  Google Scholar 

  240. Cornell, R. B. & Ridgway, N. D. CTP:phosphocholine cytidylyltransferase: function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis. Prog. Lipid Res. 59, 147–171 (2015).

    CAS  PubMed  Google Scholar 

  241. Kent, C. Regulatory enzymes of phosphatidylcholine biosynthesis: a personal perspective. Biochim. Biophys. Acta 1733, 53–66 (2005).

    CAS  PubMed  Google Scholar 

  242. Infante, J. P. & Kinsella, J. E. Control of phosphatidylcholine synthesis and the regulatory role of choline kinase in rat liver. Evidence from essential-fatty acid-deficient rats. Biochem. J. 176, 631–633 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Yu, Y., Sreenivas, A., Ostrander, D. B. & Carman, G. M. Phosphorylation of Saccharomyces cerevisiae choline kinase on Ser30 and Ser85 by protein kinase A regulates phosphatidylcholine synthesis by the CDP–choline pathway. J. Biol. Chem. 277, 34978–34986 (2002).

    CAS  PubMed  Google Scholar 

  244. Bi, J. et al. Oncogene amplification in growth factor signaling pathways renders cancers dependent on membrane lipid remodeling. Cell Metab. 30, 525–538 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Desai, A. J. & Miller, L. J. Changes in the plasma membrane in metabolic disease: impact of the membrane environment on G-protein-coupled receptor structure and function. Br. J. Pharmacol. 175, 4009–4025 (2018).

    CAS  PubMed  Google Scholar 

  246. Arish, M. et al. Orchestration of membrane receptor signaling by membrane lipids. Biochimie 113, 111–124 (2015).

    CAS  PubMed  Google Scholar 

  247. Volmer, R., van der Ploeg, K. & Ron, D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl Acad. Sci. USA 110, 4628–4633 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Wang, B. & Tontonoz, P. Phospholipid remodeling in physiology and disease. Annu. Rev. Physiol. 81, 165–188 (2019).

    PubMed  Google Scholar 

  249. O’Donnell, V. B. New appreciation for an old pathway: the Lands cycle moves into new arenas in health and disease. Biochem. Soc. Trans. 50, 1–11 (2022).

    PubMed  PubMed Central  Google Scholar 

  250. Lands, W. E. Stories about acyl chains. Biochim. Biophys. Acta 1483, 1–14 (2000).

    CAS  PubMed  Google Scholar 

  251. Shayman, J. A. & Tesmer, J. J. G. Lysosomal phospholipase A2. Biochim. Biophys. Acta Mol. Cell. Biol. Lipids 1864, 932–940 (2019).

    CAS  PubMed  Google Scholar 

  252. Hornburg, D. et al. Dynamic lipidome alterations associated with human health, disease and ageing. Nat. Metab. 5, 1578–1594 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Broadfield, L. A., Pane, A. A., Talebi, A., Swinnen, J. V. & Fendt, S. M. Lipid metabolism in cancer: new perspectives and emerging mechanisms. Dev. Cell 56, 1363–1393 (2021).

    CAS  PubMed  Google Scholar 

  254. Settembre, C. & Perera, R. M. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat. Rev. Mol. Cell Biol. 25, 223–245 (2024).

    CAS  PubMed  Google Scholar 

  255. Feingold, K. R. Introduction to lipids and lipoproteins. In Endotext (eds. Feingold, K. R. et al.) (MDText.com, 2000).

  256. Thelen, A. M. & Zoncu, R. Emerging roles for the lysosome in lipid metabolism. Trends Cell Biol. 27, 833–850 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Hirabayashi, T. et al. Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups. Cell Rep. 42, 111940 (2023).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all members of the Birsoy and Abu-Remaileh laboratories for their feedback and discussions. T.C.K. is supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) F32DK127836 and K99DK140517. S.S. is supported by NIH T32GM007365 and 5T32GM139791-03. M.A.-R. is supported by NIH DP-CA271386, Michael J. Fox Foundation ASAP-000463 and Beat Batten NCL Foundation NCL-Stiftung. K.B. is supported by NIH/NIDDK R01DK123323-01 and R01DK140337-01.

Author information

Author notes

  1. These authors contributed equally: Timothy C. Kenny, Samantha Scharenberg.

Authors and Affiliations

  1. Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA

    Timothy C. Kenny & Kıvanç Birsoy

  2. Department of Chemical Engineering, Stanford University, Stanford, CA, USA

    Samantha Scharenberg & Monther Abu-Remaileh

  3. Department of Genetics, Stanford University, Stanford, CA, USA

    Samantha Scharenberg & Monther Abu-Remaileh

  4. The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA, USA

    Samantha Scharenberg & Monther Abu-Remaileh

  5. Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA

    Samantha Scharenberg

  6. Stanford Biophysics Program, Stanford University, Stanford, CA, USA

    Samantha Scharenberg

  7. The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA

    Monther Abu-Remaileh

Authors
  1. Timothy C. Kenny
    View author publications

    Search author on:PubMed Google Scholar

  2. Samantha Scharenberg
    View author publications

    Search author on:PubMed Google Scholar

  3. Monther Abu-Remaileh
    View author publications

    Search author on:PubMed Google Scholar

  4. Kıvanç Birsoy
    View author publications

    Search author on:PubMed Google Scholar

Contributions

T.C.K. and S.S. performed the literature review and drafted an outline of the manuscript with input from M.A.-R. and K.B. T.C.K. and S.S. wrote the first draft of the manuscript and generated all figures. M.A.-R. and K.B. provided critical feedback and assisted in editing of the final manuscript.

Corresponding authors

Correspondence to Monther Abu-Remaileh or Kıvanç Birsoy.

Ethics declarations

Competing interests

M.A.-R. is a scientific advisory board member of Lycia Therapeutics. K.B. is a scientific advisor to Nanocare Pharmaceuticals and Atavistik Bio. T.C.K. and S.S. declare no interests.

Peer review

Peer review information

Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Alfredo Giménez-Cassina, in collaboration with the Nature Metabolism team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kenny, T.C., Scharenberg, S., Abu-Remaileh, M. et al. Cellular and organismal function of choline metabolism. Nat Metab 7, 35–52 (2025). https://doi.org/10.1038/s42255-024-01203-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s42255-024-01203-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing