Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities.
Journal
Seminars in liver disease
ISSN: 1098-8971
Titre abrégé: Semin Liver Dis
Pays: United States
ID NLM: 8110297
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
pubmed:
22
7
2021
medline:
26
11
2021
entrez:
21
7
2021
Statut:
ppublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
Identifiants
pubmed: 34289507
doi: 10.1055/s-0041-1731707
pmc: PMC8492195
doi:
Substances chimiques
Bile Acids and Salts
0
Receptors, Cytoplasmic and Nuclear
0
farnesoid X-activated receptor
0C5V0MRU6P
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
461-475Informations de copyright
The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Déclaration de conflit d'intérêts
Michael Trauner reports personal fees from Albireo; grants, personal fees, and other from Gilead; grants, personal fees, and other from Falk Foundation; personal fees from Novartis; grants, personal fees, and other from Intercept; grants, personal fees, and other from MSD; personal fees from Phenex; grants from Takeda; personal fees from BMS; personal fees from Boehringer Ingelheim; personal fees from BioMX; personal fees from Genfit; personal fees from Regulus; other from Abbvie; grants from Cymabay; personal fees from Shire; personal fees from Pliant outside the submitted work. In addition, he has a patent Medical use of nor-UDCA (WO2006119803 and WO20099013334 licensed to Medical University of Graz.
Références
Sci Transl Med. 2016 Sep 21;8(357):357ra122
pubmed: 27655848
J Gastroenterol Hepatol. 2018 Jan;33(1):70-85
pubmed: 28670712
Liver Int. 2020 Jun;40(6):1366-1377
pubmed: 32141703
Hepatology. 2019 Jan;69(1):420-430
pubmed: 30070383
Compr Physiol. 2013 Jul;3(3):1191-212
pubmed: 23897684
J Biol Chem. 2013 Apr 26;288(17):11761-70
pubmed: 23460643
Science. 2013 Sep 6;341(6150):1241214
pubmed: 24009397
Am J Physiol Gastrointest Liver Physiol. 2010 Mar;298(3):G440-5
pubmed: 20093562
JHEP Rep. 2020 Oct 09;2(6):100192
pubmed: 33163950
J Lipid Res. 2018 Jun;59(6):982-993
pubmed: 29559521
Dig Dis Sci. 2015 Nov;60(11):3318-28
pubmed: 26138654
Lancet Gastroenterol Hepatol. 2019 Oct;4(10):781-793
pubmed: 31345778
Gut. 2018 Oct;67(10):1881-1891
pubmed: 28774887
Semin Liver Dis. 2015 Aug;35(3):221-35
pubmed: 26378640
J Hepatol. 2011 May;54(5):1011-9
pubmed: 21145828
Mol Cell. 2000 Sep;6(3):507-15
pubmed: 11030331
PLoS One. 2019 Jan 25;14(1):e0211348
pubmed: 30682184
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3920-5
pubmed: 16473946
J Hepatol. 2019 Mar;70(3):531-544
pubmed: 30414863
Nat Rev Gastroenterol Hepatol. 2014 Jan;11(1):55-67
pubmed: 23982684
Dig Dis. 2017;35(3):288-292
pubmed: 28249255
World J Hepatol. 2015 Dec 8;7(28):2811-8
pubmed: 26668692
Gastroenterology. 2007 Jul;133(1):80-90
pubmed: 17631134
Hepatology. 2001 Mar;33(3):633-46
pubmed: 11230744
Cell Metab. 2013 Feb 5;17(2):225-35
pubmed: 23395169
Microorganisms. 2020 Jun 19;8(6):
pubmed: 32575352
Trends Endocrinol Metab. 2012 Aug;23(8):365-71
pubmed: 22609053
Science. 1999 May 21;284(5418):1362-5
pubmed: 10334992
Curr Atheroscler Rep. 2015 Apr;17(4):500
pubmed: 25690590
J Hepatol. 2017 Apr;66(4):724-733
pubmed: 27993716
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2606-11
pubmed: 18029909
Gastroenterology. 2017 May;152(7):1679-1694.e3
pubmed: 28214524
Hepatology. 2013 Apr;57(4):1394-406
pubmed: 23299969
Lancet. 2019 Dec 14;394(10215):2184-2196
pubmed: 31813633
Nature. 2020 May;581(7809):475-479
pubmed: 32461639
Hepatology. 2019 Jun;69(6):2672-2682
pubmed: 30179269
Br J Pharmacol. 2018 Feb;175(3):469-484
pubmed: 29139555
Nature. 2006 Jan 26;439(7075):484-9
pubmed: 16400329
Hepatology. 2008 Nov;48(5):1632-43
pubmed: 18972444
J Clin Invest. 2006 Apr;116(4):1102-9
pubmed: 16557297
J Hepatol. 2019 Apr;70(4):735-744
pubmed: 30529590
Nat Commun. 2013;4:2384
pubmed: 24064762
Biochem Pharmacol. 2013 Dec 1;86(11):1517-24
pubmed: 23988487
Hepatology. 2009 Sep;50(3):861-70
pubmed: 19582812
Liver Int. 2018 Feb;38(2):342-349
pubmed: 28746779
Science. 2006 Aug 25;313(5790):1137-40
pubmed: 16931765
J Biol Chem. 2016 Jan 29;291(5):2397-411
pubmed: 26655953
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1006-11
pubmed: 16410358
FEMS Microbiol Rev. 2005 Sep;29(4):625-51
pubmed: 16102595
Gastroenterology. 2020 May;158(7):1999-2014.e1
pubmed: 32044314
Pharmacol Rev. 2014 Oct;66(4):948-83
pubmed: 25073467
J Hepatol. 2017 Jul;67(1):145-172
pubmed: 28427765
Handb Exp Pharmacol. 2019;256:167-205
pubmed: 31197565
J Hepatol. 2016 Jun;64(6):1388-402
pubmed: 27062661
Hepatol Res. 2011 Jul;41(7):647-59
pubmed: 21711424
J Hepatol. 2011 Jun;54(6):1263-72
pubmed: 21145931
J Hepatol. 2015 Jun;62(6):1398-404
pubmed: 25617503
J Biol Chem. 2012 Jul 13;287(29):24784-94
pubmed: 22619174
Hepatol Int. 2020 Sep;14(5):677-689
pubmed: 32653991
J Clin Endocrinol Metab. 2017 Oct 1;102(10):3783-3794
pubmed: 28938455
Hepatology. 2021 Feb;73(2):625-643
pubmed: 33169409
J Lipid Res. 2009 Jun;50(6):1090-100
pubmed: 19174369
Semin Liver Dis. 2015 Aug;35(3):236-49
pubmed: 26378641
J Hepatol. 2009 Aug;51(2):380-8
pubmed: 19501927
Gastroenterology. 2016 Nov;151(5):845-859
pubmed: 27639801
Hepatology. 2018 Jan;67(1):328-357
pubmed: 28714183
Diabetes. 2013 Dec;62(12):4184-91
pubmed: 23884887
Sci Rep. 2017 Dec 8;7(1):17193
pubmed: 29222421
Sci Rep. 2018 Nov 21;8(1):17210
pubmed: 30464200
Clin Transl Gastroenterol. 2020 Mar;11(3):e00131
pubmed: 32352707
Nat Med. 2019 Dec;25(12):1885-1893
pubmed: 31792455
Hepatology. 2017 Apr;65(4):1393-1404
pubmed: 27997980
Gut. 2004 Dec;53(12):1837-43
pubmed: 15542525
J Lipid Res. 2010 Apr;51(4):771-84
pubmed: 19783811
Pharmacol Rev. 1995 Mar;47(1):1-23
pubmed: 7784477
Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G725-34
pubmed: 18687752
Cancer Res. 2014 Jun 15;74(12):3306-16
pubmed: 24728076
PLoS One. 2020 Aug 12;15(8):e0234750
pubmed: 32785220
Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2020-30
pubmed: 16037564
Diabetes. 2017 Mar;66(3):613-626
pubmed: 28223344
Mol Endocrinol. 2003 Feb;17(2):259-72
pubmed: 12554753
Hepatology. 2012 Jan;55(1):267-76
pubmed: 21932398
Cell Cycle. 2012 Jul 15;11(14):2699-710
pubmed: 22751440
World J Gastroenterol. 2018 Jan 14;24(2):195-210
pubmed: 29375205
J Hepatol. 2019 Mar;70(3):483-493
pubmed: 30414864
Hepatology. 2016 Dec;64(6):2015-2027
pubmed: 27639192
Gastroenterology. 2015 Mar;148(3):547-55
pubmed: 25461851
Hepatology. 1996 Jun;23(6):1464-7
pubmed: 8675165
Cell. 2000 Sep 15;102(6):731-44
pubmed: 11030617
J Biochem Mol Toxicol. 2018 Mar;32(3):e22035
pubmed: 29341352
Hepatology. 2009 Jun;49(6):1904-12
pubmed: 19434741
Eur J Gastroenterol Hepatol. 2011 May;23(5):382-8
pubmed: 21448070
Hepatology. 2020 Apr;71(4):1198-1212
pubmed: 30805949
Gut. 2021 May;70(5):962-969
pubmed: 32938692
Gut. 2017 Jun;66(6):1138-1153
pubmed: 28314735
Hepatology. 2009 Jan;49(1):297-305
pubmed: 19085950
J Hepatol. 2020 Jul;73(1):202-209
pubmed: 32278004
Annu Rev Pathol. 2018 Jan 24;13:321-350
pubmed: 29414249
J Clin Invest. 2015 Jan;125(1):386-402
pubmed: 25500885
Gut. 2011 Mar;60(3):387-96
pubmed: 21115542
J Biol Chem. 2003 Dec 19;278(51):51085-90
pubmed: 14527955
Hepatology. 2014 Dec;60(6):1942-56
pubmed: 24753158
Metabolism. 2011 Mar;60(3):404-13
pubmed: 20423748
Nat Commun. 2020 Jan 13;11(1):240
pubmed: 31932588
Cell Metab. 2009 Sep;10(3):167-77
pubmed: 19723493
Am J Physiol Heart Circ Physiol. 2009 Feb;296(2):H272-81
pubmed: 19028791
Biochem Biophys Res Commun. 2007 Mar 2;354(1):154-9
pubmed: 17214962
Cell Metab. 2012 May 2;15(5):665-74
pubmed: 22560219
Clin Gastroenterol Hepatol. 2021 Mar;19(3):580-589.e5
pubmed: 32531342
J Biol Chem. 2001 Aug 3;276(31):28857-65
pubmed: 11387316
Hepatology. 2009 Apr;49(4):1228-35
pubmed: 19185005
Hepatology. 2017 Feb;65(2):722-738
pubmed: 27981592
Hepatology. 1992 Aug;16(2):426-32
pubmed: 1639353
J Hepatol. 2017 Jun;66(6):1300-1312
pubmed: 28267621
Gastroenterology. 2001 Jul;121(1):140-7
pubmed: 11438503
Mol Cell. 1999 May;3(5):543-53
pubmed: 10360171
Curr Opin Gastroenterol. 2014 May;30(3):332-8
pubmed: 24625896
Clin Biochem. 2012 Jun;45(9):655-8
pubmed: 22465275
PLoS One. 2013 Jun 26;8(6):e67160
pubmed: 23840612
Nat Rev Gastroenterol Hepatol. 2018 Feb;15(2):111-128
pubmed: 29018272
Am J Physiol Gastrointest Liver Physiol. 2013 Feb 15;304(4):G371-80
pubmed: 23257920
Cell Mol Life Sci. 2015 May;72(9):1631-50
pubmed: 25511198
Liver Int. 2018 Nov;38(11):2082-2090
pubmed: 29630771
Eur J Gastroenterol Hepatol. 2008 Jun;20(6):519-25
pubmed: 18467911
Hepatol Commun. 2020 Aug 28;4(11):1637-1650
pubmed: 33163834
PLoS One. 2016 May 20;11(5):e0151829
pubmed: 27203081
Ann Intern Med. 1994 Sep 15;121(6):416-22
pubmed: 8053615
J Pharmacol Exp Ther. 2012 Dec;343(3):556-67
pubmed: 22918042
Diabetes. 2010 Aug;59(8):1899-905
pubmed: 20522594
J Hepatol. 2005 Dec;43(6):1021-30
pubmed: 16139386
Am J Pathol. 2011 Jan;178(1):175-86
pubmed: 21224055
J Clin Pharmacol. 1981 Oct;21(10):436-42
pubmed: 7031100
Arch Intern Med. 1999 Dec 13-27;159(22):2647-58
pubmed: 10597755
J Clin Invest. 2004 May;113(10):1408-18
pubmed: 15146238
Int J Mol Sci. 2018 Jul 16;19(7):
pubmed: 30013008
Clin Pharmacol Drug Dev. 2020 Apr;9(3):395-410
pubmed: 31823525
J Hepatol. 2018 Feb;68(2):280-295
pubmed: 29154964
Hepatology. 2017 Jan;65(1):350-362
pubmed: 27358174
Science. 1999 May 21;284(5418):1365-8
pubmed: 10334993
Am J Pathol. 2015 Feb;185(2):409-19
pubmed: 25592258
Cell Metab. 2011 Jun 8;13(6):729-38
pubmed: 21641554
Nat Med. 2019 Jul;25(7):1104-1109
pubmed: 31235964
Lancet. 2018 Mar 24;391(10126):1174-1185
pubmed: 29519502
Mol Endocrinol. 2011 Jun;25(6):1066-71
pubmed: 21454404
Am J Pathol. 2009 Dec;175(6):2392-405
pubmed: 19910507
Gastroenterology. 2002 Oct;123(4):1238-51
pubmed: 12360485
Nat Rev Dis Primers. 2015 Dec 17;1:15080
pubmed: 27188459
Gut. 2017 Mar;66(3):429-437
pubmed: 26740296
Hepatology. 2020 Jul;72(1):58-71
pubmed: 32115759
Gut. 2011 Apr;60(4):463-72
pubmed: 21242261
Hepatology. 2014 Jun;59(6):2286-98
pubmed: 24259407
Clin Gastroenterol Hepatol. 2006 Dec;4(12):1537-43
pubmed: 17162245
Sci Rep. 2018 May 25;8(1):8157
pubmed: 29802399
Gastroenterology. 2021 Jan;160(1):219-231.e1
pubmed: 32781086
J Biol Chem. 2020 Apr 3;295(14):4733-4747
pubmed: 32075905
Gastroenterology. 2007 Feb;132(2):709-19
pubmed: 17258737
Hepatology. 2012 Sep;56(3):922-32
pubmed: 22431131
Nat Med. 2015 Feb;21(2):159-65
pubmed: 25559344
Hepatology. 2004 Jul;40(1):149-56
pubmed: 15239098
Hepatology. 2018 Feb;67(2):534-548
pubmed: 28696585
Front Pharmacol. 2018 Dec 03;9:1382
pubmed: 30559664
Nature. 2013 Jul 4;499(7456):97-101
pubmed: 23803760
Hepatology. 1988 Mar-Apr;8(2):332-40
pubmed: 2965676
J Med Chem. 2017 Dec 28;60(24):9960-9973
pubmed: 29148806
Hepatology. 2021 Jan;73(1):126-143
pubmed: 32794259
J Hepatol. 2020 Aug;73(2):231-240
pubmed: 32234329
Clin Exp Rheumatol. 2016 Jul-Aug;34(4 Suppl 98):25-31
pubmed: 27586800
Clin Pharmacol Drug Dev. 2013 Jul;2(3):213-22
pubmed: 27121782
Hepatol Commun. 2019 May 17;3(8):1085-1097
pubmed: 31388629
Gastroenterology. 2017 Apr;152(5):1090-1099.e1
pubmed: 28088461
Curr Hepatol Rep. 2017;16(4):391-397
pubmed: 29984130
Gut. 2008 Jun;57(6):807-13
pubmed: 18270241
Gastroenterology. 2013 Sep;145(3):574-82.e1
pubmed: 23727264
Science. 2011 Mar 25;331(6024):1621-4
pubmed: 21436455
Hepatology. 2003 Mar;37(3):551-7
pubmed: 12601352
Front Biosci (Landmark Ed). 2009 Jan 01;14(7):2584-98
pubmed: 19273221
Sci Rep. 2016 Sep 16;6:33453
pubmed: 27634375
Am J Med. 1987 Aug;83(2):243-8
pubmed: 3618626
Drug Metab Dispos. 2015 Jun;43(6):829-35
pubmed: 25788542
Curr Diab Rep. 2010 Feb;10(1):70-7
pubmed: 20425070
Hepatology. 2010 Aug;52(2):472-9
pubmed: 20683947
Toxicology. 1991;68(3):207-15
pubmed: 1654601
Hepatology. 2004 Mar;39(3):770-8
pubmed: 14999696
JAMA. 1965 Apr 26;192:289-93
pubmed: 14271976
Lancet. 2015 Mar 14;385(9972):956-65
pubmed: 25468160
Semin Liver Dis. 2016 Feb;36(1):69-86
pubmed: 26870934
Mol Cell. 2000 Sep;6(3):517-26
pubmed: 11030332
Lipids. 2009 Jun;44(6):521-6
pubmed: 19408031