Bile Acids and Their Value for Central Nervous System
https://doi.org/10.22416/1382-4376-2021-31-5-7-15
Abstract
Aim. A review to highlight the bile acids importance as steroid mediators of nervous system activity and show the nervous system involvement in cholesterol metabolism and bile acids production.
Key points. Presence of bile acid membrane and nuclear receptors and their activation role in mediating manifold metabolic processes have been established in various organs and tissues. Bile acid transporters are discovered in CNS. The animal brain under physiological conditions was found to contain about 20 bile acid types of likely innate origin suggested by their high contents; the bile acids spectrum in CNS differs significantly from blood plasma. Clinical and experimental works are conclusive about the CNS bile acids influence on mitochondrial membrane, their antioxidative role and, probably, steroid-mediator involvement in indirect regulation of memory, attention, motor functions and appetite.
Conclusion. Bile acids act as pleiotropic signalling molecules affecting various tissues. The presence in CNS of various bile acid synthesis-related receptors and enzymes indicates their value in brain functioning and warrants research into their metabolism.
About the Authors
Yu. O. Shulpekova
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Yuliya O. Shulpekova — Cand. Sci. (Med.), Assoc. Prof., Chair of Internal Disease Propaedeutics, Gastroenterology and Hepatology
119435, Moscow, Pogodinskaya str., 1, bld. 1
P. E. Tkachenko
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Petr E. Tkachenko — Cand. Sci. (Med.), Physician, Department of Hepatology, Vasilenko Clinic of Internal Disease Propaedeutics, Gastroenterology and Hepatology
119435, Moscow, Pogodinskaya str., 1, bld. 1
E. N. Shirokova
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Elena N. Shirokova — Dr. Sci. (Med.), Prof., Chair of Internal Disease Propaedeutics, Gastroenterology and Hepatology
119435, Moscow, Pogodinskaya str., 1, bld. 1
I. V. Damulin
Moscow Research Institute of Psychiatry — Branch of Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Ministry of Health of the Russian Federation
Russian Federation
Russian Federation
Igor V. Damulin — Dr. Sci. (Med.), Prof., Leading Researcher, Sector of Exogenous Organic Disorders and Epilepsy, Department of Clinical and Pathogenetic Research in Psychiatry
107076, Moscow, Poteshnaya str., 3, r. 10
References
1. Chiang J.Y.L., Ferrell J.M. Bile Acids as Metabolic Regulators and Nutrient Sensors. Annu Rev Nutr. 2019;39:175– 200. DOI: 10.1146/annurev-nutr-082018-124344
2. Sonne D.P., van Nierop F.S., Kulik W., Soeters M.R., Vilsbøll T., Knop F.K. Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2016;101(8):3002–9. DOI: 10.1210/jc.2016-1607
3. Mertens K.L., Kalsbeek A., Soeters M.R., Eggink H.M. Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System. Front Neurosci. 2017 Nov 7;11:617. DOI: 10.3389/fnins.2017.00617
4. Krähenbühl S., Talos C., Fischer S., Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology. 1994 Feb;19(2):471–9. DOI: 10.1002/hep.1840190228
5. Tsuei J., Chau T., Mills D., Wan Y.J. Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer. Exp Biol Med (Maywood). 2014 Nov;239(11):1489–504. DOI: 10.1177/1535370214538743
6. Jia W., Xie G., Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018 Feb;15(2):111–28. DOI: 10.1038/nrgastro.2017.119
7. Kiriyama Y., Nochi H. The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules. 2019;9(6):232. DOI: 10.3390/biom9060232
8. Ma X., Idle J.R., Gonzalez F.J. The pregnane X receptor: from bench to bedside. Expert Opin Drug Metab Toxicol. 2008;4(7):895–908. DOI: 10.1517/17425255.4.7.895
9. De Magalhaes Filho C.D., Downes M., Evans R.M. Farnesoid X Receptor an Emerging Target to Combat Obesity. Dig Dis. 2017;35(3):185–90. DOI: 10.1159/000450909
10. Mano N., Goto T., Uchida M., Nishimura K., Ando M., Kobayashi N., et al. Presence of protein-bound unconjugated bile acids in the cytoplasmic fraction of rat brain. J Lipid Res. 2004;45(2):295–300. DOI: 10.1194/jlr.M300369-JLR200
11. Zheng X., Chen T., Zhao A., Wang X., Xie G., Huang F., et al. The Brain Metabolome of Male Rats across the Lifespan. Sci Rep. 2016 Apr 11;6:24125. DOI: 10.1038/srep24125
12. Higashi T., Watanabe S., Tomaru K., Yamazaki W., Yoshizawa K., Ogawa S., et al. Unconjugated bile acids in rat brain: Analytical method based on LC/ESI-MS/MS with chemical derivatization and estimation of their origin by comparison to serum levels. Steroids. 2017;125:107–13. DOI: 10.1016/j.steroids.2017.07.001
13. Pan X., Elliott C.T., McGuinness B., Passmore P., Kehoe P.G., Hölscher C., et al. Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer’s Disease. Metabolites. 2017;7(2):28. DOI: 10.3390/metabo7020028
14. Meaney S., Heverin M., Panzenboeck U., Ekström L., Axelsson M., Andersson U., et al. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid. J Lipid Res. 2007;48(4):944–51. DOI: 10.1194/jlr.M600529-JLR200
15. Schmidt D.R., Schmidt S., Holmstrom S.R., Makishima M., Ruth Yu.T., Cummins C.L., et al. AKR1B7 is induced by the farnesoid X receptor and metabolizes bile acids. J Biol Chem. 2011;286(4):2425–32. DOI: 10.1074/jbc.M110.181230
16. Huang F., Wang T., Lan Y., Yang L., Pan W., Zhu Y., et al. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Front Behav Neurosci. 2015;9:70. DOI: 10.3389/fnbeh.2015.00070
17. Di Somma C., Scarano E., Barrea L., Zhukouskaya V.V., Savastano S., Mele C, et al. Vitamin D and Neurological Diseases: An Endocrine View. International Journal of Molecular Sciences. 2017;18(11):2482. DOI: 10.3390/ ijms18112482
18. Eyles D.W., Smith S., Kinobe R., Hewison M., McGrath J.J. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. Journal of Chemical Neuroanatomy. 2005;29(1):21–30. DOI: 10.1016/j.jchemneu.2004.08.006
19. Sheptulina A.F., Shirokova Ye.N., Ivashkin V.T. Nuclear receptors in regulation of bile acids transport and metabolism. Rus J Gastroenterol Hepatol Coloproctol. 2013;5:32–45 (In Russ.).
20. Buell J.S., Dawson-Hughes B. Vitamin D and Neurocognitive Dysfunction: Preventing “D”ecline? Molecular aspects of medicine. 2008;29(6):415–22. DOI: 10.1016/j.mam.2008.05.001
21. Reddy D.S. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113–37. DOI: 10.1016/B978-0-444-53630-3.00008-7
22. Keitel V., Görg B., Bidmon H.J., Zemtsova I., Spomer L., Zilles K., et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia. 2010;58(15):1794–805. DOI: 10.1002/glia.21049
23. Schubring S.R., Fleischer W., Lin J.S., Haas H.L., Sergeeva O.A. The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA(A) receptors. Neurosci Lett. 2012;506(2):322–6. DOI: 10.1016/j.neulet.2011.11.036
24. Yanovsky Y., Schubring S.R., Yao Q., Zhao Y., Li S., May A., et al. Waking action of ursodeoxycholic acid (UDCA) involves histamine and GABAA receptor block. PLoS One. 2012;7(8):e42512. DOI: 10.1371/journal.pone.0042512
25. Silva S.L., Vaz A.R., Diógenes M.J., van Rooijen N., Sebastião A.M., Fernandes A., et al. Neuritic growth impairment and cell death by unconjugated bilirubin is mediated by NO and glutamate, modulated by microglia, and prevented by glycoursodeoxycholic acid and interleukin-10. Neuropharmacology. 2012;62(7):2398–408. DOI: 10.1016/j.neuropharm.2012.02.002
26. Palmela I., Correia L., Silva R.F., Sasaki H., Kim K.S., Brites D., et al. Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study. Front Neurosci. 2015;9:80. DOI: 10.3389/fnins.2015.00080
27. Quinn M., McMillin M., Galindo C., Frampton G., Pae H.Y., DeMorrow S. Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms. Dig Liver Dis. 2014;46(6):527–34. DOI: 10.1016/j.dld.2014.01.159
28. Ljubuncic P., Said O., Ehrlich Y., Meddings J.B., Shaffer E.A., Bomzon A. On the in vitro vasoactivity of bile acids. Br J Pharmacol. 2000;131(3):387–98. DOI: 10.1038/sj.bjp.0703554
29. Sun D., Gu G., Wang J., Chai Y., Fan Y., Yang M., et al. Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation. Front Cell Neurosci. 2017;11:193. DOI: 10.3389/fncel.2017.00193
30. Ackerman H.D., Gerhard G.S. Bile Acids in Neurodegenerative Disorders. Frontiers in Aging Neuroscience. 2016;8:263. DOI: 10.3389/fnagi.2016.00263
31. Romero-Ramírez L., Nieto-Sampedro M., Yanguas-Casás N. Tauroursodeoxycholic acid: more than just a neuroprotective bile conjugate. Neural Regen Res. 2017;12(1):62– 3. DOI: 10.4103/1673-5374.198979
32. Payne T., Sassani M., Buckley E., Moll S., Anton A., Appleby M., et al. Ursodeoxycholic acid as a novel diseasemodifying treatment for Parkinson’s disease: protocol for a two-centre, randomised, double-blind, placebo-controlled trial, The ‘UP’ study. BMJ Open. 2020;10(8):e038911. DOI: 10.1136/bmjopen-2020-038911
33. McMillin M., Frampton G., Tobin R., Dusio G., Smith J., Shin H., et al. TGR5 signaling reduces neuroinflammation during hepatic encephalopathy. J Neurochem. 2015;135(3):565–76. DOI: 10.1111/jnc.13243
34. Nizamutdinov D., DeMorrow S., McMillin M., Kain J., Mukherjee S., Zeitouni S., et al. Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury. Sci Rep. 2017;7:40112. DOI: 10.1038/srep40112
35. Klaassen C.D., Aleksunes L.M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010;62(1):1–96. DOI: 10.1124/pr.109.002014
36. Tripodi V., Contin M., Fernández M.A., Lemberg A. Bile acids content in brain of common duct ligated rats. Ann Hepatol. 2012;11(6):930–4.
37. Kremer A.E., Namer B., Bolier R., Fischer M.J., Oude Elferink R.P., Beuers U. Pathogenesis and Management of Pruritus in PBC and PSC. Dig Dis. 2015;33 Suppl 2:164-75. DOI: 10.1159/000440829
38. Yu H., Zhao T., Liu S., Wu Q., Johnson O., Wu Z., et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. Elife. 2019;8:e48431. DOI: 10.7554/eLife.48431
39. Yang C., Jin C., Li X., Wang F., McKeehan W.L., Luo Y. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One. 2012;7(3):e33870. DOI: 10.1371/journal.pone.0033870
40. Kuhre R.E., Wewer Albrechtsen N.J., Larsen O., Jepsen S.L., Balk-Møller E., Andersen D.B., et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018;11:84–95. DOI: 10.1016/j.molmet.2018.03.007
41. Thomas C., Gioiello A., Noriega L., Strehle A., Oury J., Rizzo G., et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10(3):167–77. DOI: 10.1016/j.cmet.2009.08.001
42. Holst J.J. Incretin hormones and the satiation signal. Int J Obes (Lond). 2013;37(9):1161–8. DOI: 10.1038/ijo.2012.208
43. Chepurny O.G., Holz G.G. Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci. 2014;121:23– 65. DOI: 10.1016/B978-0-12-800101-1.00002-8
44. Lin B., Wang Y., Zhang P., Yuan Y., Zhang Y., Chen G. Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy. J Headache Pain. 2020 Aug 17;21(1):103. DOI: 10.1186/s10194-020-01170-x. PMID: 32807072. PMCID: PMC7433133
45. Meaney S., Heverin M., Panzenboeck U., Ekström L., Axelsson M., Andersson U., et al. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid. J Lipid Res. 2007;48(4):944–51.
Review
For citations:
Shulpekova Yu.O., Tkachenko P.E., Shirokova E.N., Damulin I.V. Bile Acids and Their Value for Central Nervous System. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(5):7-15. (In Russ.) https://doi.org/10.22416/1382-4376-2021-31-5-7-15
Views:
1305
Email this article 
