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담즙산과 대사질환

Bile Acids and the Metabolic Disorders

  • 투고 : 2018.11.30
  • 심사 : 2018.12.17
  • 발행 : 2018.12.29

초록

Bile acids are major constituents of bile and known to help absorb dietary fat and fat-soluble vitamins in the gastrointestinal tract. In the past few decades, many studies have shown that bile acids not only play a role in fat digestion but also function as broad range of signal transduction hormones by binding to various receptors present in cell membranes or nuclei. Bile acid receptors are distributed in a wide range of organs and tissues in the human body. They perform multitudes of physiological functions with complex mechanisms. When bile acids bind to their receptors, they regulate fat and glucose metabolism in a tissue-specific way. In addition, bile acids are shown to inhibit inflammation and fibrosis in the liver. Considering the roles of bile acids as metabolic regulators, bile acids and their receptors can be very attractive targets in treating metabolic disorders. In the future, if roles of bile acids and their receptors are further clarified, they will be the novel target of drugs in the treatment of various metabolic diseases.

키워드

참고문헌

  1. Esteller A. Physiology of bile secretion. World J Gastroenterol 2008;14(37):5641-9. https://doi.org/10.3748/wjg.14.5641
  2. Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. Embo J 2006;25(7):1419-25. https://doi.org/10.1038/sj.emboj.7601049
  3. Zhu C, Fuchs C, Halilbasic E, et al. Bile acids in regulation of inflammation and immunity: friend or foe? Clin Exp Rheumatol 2016;34(4 Suppl 98):25-31.
  4. Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89(1):147-91. https://doi.org/10.1152/physrev.00010.2008
  5. Handelsman Y. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 2011;34(Suppl 2):S244-50. https://doi.org/10.2337/dc11-s237
  6. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956-65. https://doi.org/10.1016/S0140-6736(14)61933-4
  7. U.S. National Library of Medicine. Study of the effects of obeticholic acid on farnesoid X receptor expression in jejunum and on gut microbiota in morbidly obese patients and healthy volunteers. Available from https://clinicaltrialsgov/ct2/show/NCT02532335?cond=obeticholic+acid&rank=5. Accessed Aug 29, 2018.
  8. Aguiar Vallim TQ, Tarling EJ, et al. Pleiotropic roles of bile acids in metabolism. Cell Metab 2013;17(5):657-69. https://doi.org/10.1016/j.cmet.2013.03.013
  9. Han CY. Update on FXR biology: promising therapeutic target? Int J Mol Sci 2018;19(7):pii:2069.
  10. Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009;50(10):1955-66. https://doi.org/10.1194/jlr.R900010-JLR200
  11. Lazaridis KN, Gores GJ, Lindor KD. Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. J Hepatol 2001;35(1):134-46. https://doi.org/10.1016/S0168-8278(01)00092-7
  12. Monte MJ, Marin JJ, Antelo A, et al. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol 2009;15(7): 804-16. https://doi.org/10.3748/wjg.15.804
  13. Afroze S, Meng F, Jensen K, et al. The physiological roles of secretin and its receptor. Ann Transl Med 2013;1(3):29.
  14. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014;66(4):948-83. https://doi.org/10.1124/pr.113.008201
  15. Thomas C, Pellicciari R, Pruzanski M, et al. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008;7(8):678-93. https://doi.org/10.1038/nrd2619
  16. Makishima M, Lu TT, Xie W, et al. Vitamin D receptor as an intestinal bile acid sensor. Science 2002;296(5571):1313-6. https://doi.org/10.1126/science.1070477
  17. Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013;368(1-2):17-29. https://doi.org/10.1016/j.mce.2012.05.004
  18. Claudel T, Staels B, Kuipers F. The farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 2005;25(10):2020-30. https://doi.org/10.1161/01.ATV.0000178994.21828.a7
  19. Zhang Y, Kast-Woelbern HR, Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 2003;278(1):104-10. https://doi.org/10.1074/jbc.M209505200
  20. Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated mile acid sensing controls glucose homeostasis. Cell Metab 2009;10(3):167-77. https://doi.org/10.1016/j.cmet.2009.08.001
  21. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278(11):9435-40. https://doi.org/10.1074/jbc.M209706200
  22. Massotte, Dominique, et al. Structure-function relationships in G protein-coupled receptors. In; Devi, Lakshmi A, eds. The G protein-coupled receptors handbook, 16, New York: Humana Press, 2005:3-4
  23. Forman BM, Goode E, Chen J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995;81(5):687-93. https://doi.org/10.1016/0092-8674(95)90530-8
  24. Chiang JY, Kimmel R, Weinberger C, et al. Farnesoid X receptor responds to bile acids and represses cholesterol $7{\alpha}$-hydroxylase gene (CYP7A1) transcription. J Biol Chem 2000;275(15):10918-24. https://doi.org/10.1074/jbc.275.15.10918
  25. Kim I, Ahn S-H, Inagaki T, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 2007;48(12):2664-72. https://doi.org/10.1194/jlr.M700330-JLR200
  26. Pineda Torra I, Claudel T, Duval C, et al. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 2003;17(2):259-72. https://doi.org/10.1210/me.2002-0120
  27. Cyphert HA, Ge X, Kohan AB, et al. Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem 2012;287(30):25123-38. https://doi.org/10.1074/jbc.M112.375907
  28. Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115(6):1627-35. https://doi.org/10.1172/JCI23606
  29. Claudel T, Zollner G, Wagner M, et al. Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease. Biochim Biophys Acta 2011;1812(8):867-78. https://doi.org/10.1016/j.bbadis.2010.12.021
  30. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375(7):631-43. https://doi.org/10.1056/NEJMoa1509840
  31. Lackey DE, Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol 2016;12(1):15-28. https://doi.org/10.1038/nrendo.2015.189
  32. Chavez-Talavera O, Tailleux A, Lefebvre P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Am J Gastroenterol 2017; 152(7):1679-94.e3.
  33. World health organization international obesity task force, The asianpacific perspective: redefining obesity and its treatment. Geneva: WHO Western Pacific Region, 2000;17-18.
  34. Park JH. Measuring BMI cutoff points of korean adults using morbidity of BMI-related diseases. Korean J Obesity. 2011;20(1):36-43. https://doi.org/10.7570/kjo.2011.20.1.36
  35. Hamilton MT, Hamilton DG, Zderic TW. The role of low energy expenditure and sitting on obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 2007;56(11):2655-67. https://doi.org/10.2337/db07-0882
  36. Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439(7075):484-9. https://doi.org/10.1038/nature04330
  37. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368(9548):1696-705. https://doi.org/10.1016/S0140-6736(06)69705-5
  38. Astrup A, Rossner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009;374(9701):1606-16. https://doi.org/10.1016/S0140-6736(09)61375-1
  39. Molinaro A, Wahlstrom A, Marschall HU. Role of bile acids in metabolic control. Trends Endocrinol Metab 2018;29(1):31-41. https://doi.org/10.1016/j.tem.2017.11.002
  40. Kars M, Yang L, Gregor MF, et al. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 2010;59(8):1899-905. https://doi.org/10.2337/db10-0308

피인용 문헌

  1. Bile Acid Receptors in Cholangiocyte vol.26, pp.4, 2018, https://doi.org/10.15279/kpba.2021.26.4.254