From pathogenesis to novel therapies in the treatment of primary biliary cholangitis

References

• Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: from “cirrhosis” to “cholangitis”. Dig Liver Dis. 2015 Nov;47(11):924–926.
   PubMedGoogle Scholar
• Corpechot C, Carrat F, Bahr A, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005 Feb;128(2):297–303.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Beuers U, Corpechot C, et al. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul 1;67(1):145–172.
   PubMed Web of Science ®Google Scholar
• Invernizzi P, Setchell KD, Crosignani A, et al. Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis. Hepatology. 1999 Feb 1;29(2):320–327.
   PubMed Web of Science ®Google Scholar
• Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013 Mar;144(3):560.e7–569.e7.
   PubMed Web of Science ®Google Scholar
• Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology (Baltimore MD). 2008 Sep;48(3):871–877.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009 Jun 11;360(24):2544–2555.
   PubMed Web of Science ®Google Scholar
• Liu X, Invernizzi P, Lu Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010 Aug;42(8):658–660.
   PubMed Web of Science ®Google Scholar
• Mells GF, Floyd JAB, Morley KI, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011 Apr;43(4):329–332.
   PubMed Web of Science ®Google Scholar
• Nakamura M, Nishida N, Kawashima M, et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet. 2012 Oct 5;91(4):721–728.
   PubMed Web of Science ®Google Scholar
• Juran BD, Hirschfield GM, Invernizzi P, et al. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet. 2012 Dec 1;21(23):5209–5221.
   PubMed Web of Science ®Google Scholar
• Liu JZ, Almarri MA, Gaffney DJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2012 Oct;44(10):1137–1141.
   PubMed Web of Science ®Google Scholar
• Zhang W, Sharma R, Ju S-T, et al. Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology (Baltimore Md). 2009 Feb;49(2):545–552.
   PubMed Web of Science ®Google Scholar
• Lytvyak E, Montano-Loza AJ, Mason AL. Combination antiretroviral studies for patients with primary biliary cirrhosis. World J Gastroenterol. 2016 Jan 7;22(1):349–360.
   PubMed Web of Science ®Google Scholar
• Yu S, Maiti PK, Dyson M, et al. B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J Exp Med. 2006 Feb 20;203(2):349–358.
   PubMed Web of Science ®Google Scholar
• Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010 Sep;16(9):1009–1017.
   PubMed Web of Science ®Google Scholar
• Pessach IM, Notarangelo LD. X-linked primary immunodeficiencies as a bridge to better understanding X-chromosome related autoimmunity. J Autoimmun. 2009 Aug;33(1):17–24.
   PubMed Web of Science ®Google Scholar
• Yoshida K, Yang G-X, Zhang W, et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice. Hepatology. 2009 Nov;50(5):1494–1500.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015 Apr 1;148(4):751–61.e8.
   PubMed Web of Science ®Google Scholar
• Úriz M, Sáez E, Prieto J, et al. Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat. PLoS One. 2011;6(12):e28717.
   PubMed Web of Science ®Google Scholar
• Mayo MJ, Wigg AJ, Roberts SK, et al. NGM282, A Novel Variant of FGF-19, Demonstrates Biologic Activity in Primary Biliary Cirrhosis Patients with an Incomplete Response to Ursodeoxycholic Acid: Results of a Phase 2 Multicenter, Randomized, Double Blinded, Placebo Controlled Trial: 106. Hepatology. 2015;62():263A–264A.
   Google Scholar
• Poupon R. ASBT inhibitors in cholangiopathies – good for mice, good for men? J Hepatol. 2016 Mar;64(3):537–538.
   PubMed Web of Science ®Google Scholar
• Penz-Österreicher M, Österreicher CH, Trauner M. Fibrosis in autoimmune and cholestatic liver disease. Best Pract Res. 2011 Apr;25(2):245–258.
   Web of Science ®Google Scholar
• Webb GJ, Siminovitch KA, Hirschfield GM. The immunogenetics of primary biliary cirrhosis: a comprehensive review. J Autoimmun. 2015 Nov;64:42–52.
   PubMed Web of Science ®Google Scholar
• Shimoda S, Ishikawa F, Kamihira T, et al. Autoreactive T-cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory. Gastroenterology. 2006 Aug;131(2):606–618.
   PubMed Web of Science ®Google Scholar
• Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol. 2006 Jan 21;24:65–97.
   PubMed Web of Science ®Google Scholar
• Zhao L, Tang Y, You Z, et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One. 2011 Jan;6(4):e18909.
   PubMed Web of Science ®Google Scholar
• Umemura T, Katsuyama Y, Yoshizawa K, et al. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One. 2014;9(6):e100565.
   PubMed Web of Science ®Google Scholar
• Hirschfield GM, Liu X, Han Y, et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010 Aug 18;42(8):655–657.
   PubMed Web of Science ®Google Scholar
• Donaldson PT, Baragiotta A, Heneghan MA, et al. HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study. Hepatology. 2006 Sep 1;44(3):667–674.
   PubMed Web of Science ®Google Scholar
• Dhirapong A, Lleo A, Yang G-X, et al. B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology (Baltimore Md). 2011 Feb;53(2):527–535.
   PubMed Web of Science ®Google Scholar
• Huang W, Kachapati K, Adams D, et al. Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells. J Autoimmun. 2014;50:123–134.
   PubMed Web of Science ®Google Scholar
• Lleo A, Zhang W, McDonald WH, et al. Shotgun proteomics: identification of unique protein profiles of apoptotic bodies from biliary epithelial cells. Hepatology (Baltimore Md). 2014 Oct;60(4):1314–1323.
   PubMed Web of Science ®Google Scholar
• Lleo A, Maroni L, Glaser S, et al. Role of cholangiocytes in primary biliary cirrhosis. Semin Liver Dis. 2014 Aug;34(3):273–284.
   PubMed Web of Science ®Google Scholar
• Wolfhagen FH, Van Hoogstraten HJ, Van Buuren HR, et al. Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol. 1998 Nov;29(5):736–742.
   PubMed Web of Science ®Google Scholar
• Treiber G, Malfertheiner P. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol. 2005 Oct;39(9):837–8; author reply 838.
   PubMed Web of Science ®Google Scholar
• Kaplan MM, Bonder A, Ruthazer R, et al. Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid. Dig Dis Sci. 2010 Nov;55(11):3207–3217.
   PubMed Web of Science ®Google Scholar
• Wolfhagen FH, Van Buuren HR, Schalm SW. Combined treatment with ursodeoxycholic acid and prednisone in primary biliary cirrhosis. Neth J Med. 1994 Mar;44(3):84–90.
   PubMed Web of Science ®Google Scholar
• Leuschner M, Güldütuna S, You T, et al. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol. 1996 Jul;25(1):49–57.
   PubMed Web of Science ®Google Scholar
• Mitchison HC, Bassendine MF, Malcolm AJ, et al. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology (Baltimore Md). 1989 Oct;10(4):420–429.
   PubMed Web of Science ®Google Scholar
• Ozaslan E, Efe C, Heurgué-Berlot A, et al. Factors associated with response to therapy and outcome of patients with primary biliary cirrhosis with features of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2014 May;12(5):863–869.
   PubMed Web of Science ®Google Scholar
• Rautiainen H, Kärkkäinen P, Karvonen A-L, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology (Baltimore Md). 2005 Apr;41(4):747–752.
   PubMed Web of Science ®Google Scholar
• Angulo P, Jorgensen RA, Keach JC, et al. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology (Baltimore Md). 2000 Feb;31(2):318–323.
   PubMed Web of Science ®Google Scholar
• Hempfling W, Grunhage F, Dilger K, et al. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology (Baltimore Md). 2003 Jul;38(1):196–202.
   PubMed Web of Science ®Google Scholar
• Arenas F, Hervias I, Uriz M, et al. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest. 2008 Feb;118(2):695–709.
   PubMed Web of Science ®Google Scholar
• Wang L, Wang F-S, Chang C, et al. Breach of tolerance: primary biliary cirrhosis. Semin Liver Dis. 2014;34(3):297–317.
   PubMed Web of Science ®Google Scholar
• Tiegs G, Lohse AW. Immune tolerance: what is unique about the liver. J Autoimmun. 2010 Feb;34(1):1–6.
   PubMed Web of Science ®Google Scholar
• Lleo A, Invernizzi P, Mackay I-R, et al. Etiopathogenesis of primary biliary cirrhosis. World J Gastroenterol. 2008 Jun 7;14(21):3328–3337.
   PubMed Web of Science ®Google Scholar
• Odin JA, Huebert RC, Casciola-Rosen L, et al. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J Clin Invest. 2001 Jul;108(2):223–232.
   PubMed Web of Science ®Google Scholar
• Lleo A, Selmi C, Invernizzi P, et al. Apotopes and the biliary specificity of primary biliary cirrhosis. Hepatology (Baltimore Md). 2009 Mar;49(3):871–879.
   PubMed Web of Science ®Google Scholar
• Bogdanos DP, Smyk DS, Invernizzi P, et al. Infectome: a platform to trace infectious triggers of autoimmunity. Autoimmun Rev. 2013 May;12(7):726–740.
   PubMed Web of Science ®Google Scholar
• Varyani FK, West J, Card TR. An increased risk of urinary tract infection precedes development of primary biliary cirrhosis. BMC Gastroenterol. 2011 Jan;11:95.
   PubMed Web of Science ®Google Scholar
• Mattner J, Savage PB, Leung P, et al. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe. 2008 May 15;3(5):304–315.
   PubMed Web of Science ®Google Scholar
• Shapira Y, Agmon-Levin N, Renaudineau Y, et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol. 2012 Dec;93(3):386–390.
   PubMed Web of Science ®Google Scholar
• Morshed SA, Nishioka M, Saito I, et al. Increased expression of Epstein-Barr virus in primary biliary cirrhosis patients. Gastroenterol Jpn. 1992 Dec;27(6):751–758.
   PubMedGoogle Scholar
• Sakly W, Jeddi M, Ghedira I. Anti-Saccharomyces cerevisiae antibodies in primary biliary cirrhosis. Dig Dis Sci. 2008 Jul;53(7):1983–1987.
   PubMed Web of Science ®Google Scholar
• Selmi C, Ross SR, Ansari AA, et al. Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis. Gastroenterology. 2004 Aug;127(2):493–501.
   PubMed Web of Science ®Google Scholar
• Leung PSC, Wang J, Naiyanetr P, et al. Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun. 2013;41:79–86.
   PubMed Web of Science ®Google Scholar
• Leung PSC, Park O, Tsuneyama K, et al. Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. J Immunol (Baltimore Md 1950). 2007 Aug 15;179(4):2651–2657.
   PubMed Web of Science ®Google Scholar
• Wakabayashi K, Yoshida K, Leung PSC, et al. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol. 2009 Mar;155(3):577–586.
   PubMed Web of Science ®Google Scholar
• Wakabayashi K, Lian Z-X, Leung PSC, et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology (Baltimore Md). 2008 Aug;48(2):531–540.
   PubMed Web of Science ®Google Scholar
• Rieger R, Leung PSC, Jeddeloh MR, et al. Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. J Autoimmun. 2006 Aug;27(1):7–16.
   PubMed Web of Science ®Google Scholar
• Gershwin ME, Selmi C, Worman HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology (Baltimore Md). 2005 Nov;42(5):1194–1202.
   PubMed Web of Science ®Google Scholar
• Prince MI, Ducker SJ, James OFW. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut. 2010 Apr;59(4):508–512.
   PubMed Web of Science ®Google Scholar
• Sasaki M, Yoshimura-Miyakoshi M, Sato Y, et al. A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. J Gastroenterol. 2015 Sep 1;50(9):984–995.
   PubMed Web of Science ®Google Scholar
• Sasaki M, Miyakoshi M, Sato Y, et al. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. Liver Int. 2013 Feb;33(2):312–320.
   PubMed Web of Science ®Google Scholar
• Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol. 2015 Apr;62(4):934–945.
   PubMed Web of Science ®Google Scholar
• Sasaki M, Miyakoshi M, Sato Y, et al. Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab Investig. 2010 Jun 8;90(6):835–843.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004 Jan;22:531–562.
   PubMed Web of Science ®Google Scholar
• Shevach EM. Regulatory T cells in autoimmmunity. Annu Rev Immunol. 2000 Jan;18:423–449.
   PubMed Web of Science ®Google Scholar
• Lan RY, Cheng C, Lian Z-X, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology (Baltimore Md). 2006 Apr;43(4):729–737.
   PubMed Web of Science ®Google Scholar
• Von Spee-Mayer C, Siegert E, Abdirama D, et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2016;75(7):1407–1415.
   PubMed Web of Science ®Google Scholar
• Klatzmann D, Abbas AK. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol. 2015 May;15(5):283–294.
   PubMed Web of Science ®Google Scholar
• Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013 Apr 3;5(179):179ra43.
   PubMed Web of Science ®Google Scholar
• Yang C-Y, Ma X, Tsuneyama K, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology (Baltimore Md). 2014 May;59(5):1944–1953.
   PubMed Web of Science ®Google Scholar
• Beroukhim K, Danesh M, Nguyen C, et al. A prospective, interventional assessment of the impact of ustekinumab treatment on psoriasis-related work productivity and activity impairment. J Dermatolog Treat. 2016;27(6):552–555.
   Web of Science ®Google Scholar
• Hirschfield GM, Gershwin ME, Strauss R, et al. P367 phase 2 study evaluating the efficacy and safety of ustekinumab in patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid. J Hepatol. 2014 Apr 1;60(1):S189–90.
   Web of Science ®Google Scholar
• Dhirapong A, Yang G-X, Nadler S, et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology (Baltimore Md). 2013 Feb;57(2):708–715.
   PubMed Web of Science ®Google Scholar
• Schoenberger SP, Toes RE, Van Der Voort EI, et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998 Jun 4;393(6684):480–483.
   PubMed Web of Science ®Google Scholar
• Goules A, Tzioufas AG, Manousakis MN, et al. Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases. J Autoimmun. 2006 May;26(3):165–171.
   PubMed Web of Science ®Google Scholar
• Chuang Y-H, Lian Z-X, Cheng C-M, et al. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J Autoimmun. 2005 Sep;25(2):126–132.
   PubMed Web of Science ®Google Scholar
• Hu C, Rodriguez-Pinto D, Du W, et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Investig. 2007 Dec 3;117(12):3857–3867.
   PubMed Web of Science ®Google Scholar
• Tsuda M, Moritoki Y, Lian Z-X, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology (Baltimore Md). 2012 Feb;55(2):512–521.
   PubMed Web of Science ®Google Scholar
• Myers RP, Swain MG, Lee SS, et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013 Jun;108(6):933–941.
   PubMed Web of Science ®Google Scholar
• Wallace K, Cowie DE, Konstantinou DK, et al. The PXR is a drug target for chronic inflammatory liver disease. J Steroid Biochem Mol Biol. 2010 May 31;120(2–3):137–148.
   PubMed Web of Science ®Google Scholar
• Stedman CAM, Liddle C, Coulter SA, et al. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2063–2068.
   PubMed Web of Science ®Google Scholar
• Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014 May;46(4):302–312.
   PubMedGoogle Scholar
• Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999 May;3(5):543–553.
   PubMed Web of Science ®Google Scholar
• Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell. 2000 Sep;6(3):507–515.
   PubMed Web of Science ®Google Scholar
• Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000 Sep;6(3):517–526.
   PubMed Web of Science ®Google Scholar
• Huang L, Zhao A, Lew J-L, et al. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem. 2003 Dec 19;278(51):51085–51090.
   PubMed Web of Science ®Google Scholar
• Ananthanarayanan M, Balasubramanian N, Makishima M, et al. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001 Aug 3;276(31):28857–28865.
   PubMed Web of Science ®Google Scholar
• Boyer JL, Trauner M, Mennone A, et al. Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol. 2006 Jun;290(6):G1124–G1130.
   PubMed Web of Science ®Google Scholar
• Kurosu H, Choi M, Ogawa Y, et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007 Jul 10;282(37):26687–26695.
   PubMed Web of Science ®Google Scholar
• Mencarelli A, Renga B, Migliorati M, et al. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol (Baltimore Md 1950). 2009 Nov 15;183(10):6657–6666.
   PubMed Web of Science ®Google Scholar
• Wang Y-D, Chen W-D, Wang M, et al. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology (Baltimore Md). 2008 Nov;48(5):1632–1643.
   PubMed Web of Science ®Google Scholar
• Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-Ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569–3572.
   PubMed Web of Science ®Google Scholar
• Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016 Aug 18;375(7):631–643.
   PubMed Web of Science ®Google Scholar
• Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009 Jan;89(1):147–191.
   PubMed Web of Science ®Google Scholar
• Hohenester S, De Buy Wenniger LM, Paulusma CC, et al. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology (Baltimore Md). 2012 Jan;55(1):173–183.
   PubMed Web of Science ®Google Scholar
• Rizzo G, Passeri D, De Franco F, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol. 2010 Oct;78(4):617–630.
   PubMed Web of Science ®Google Scholar
• Baghdasaryan A, Claudel T, Gumhold J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO−₃ output. Hepatology (Baltimore Md). 2011 Oct;54(4):1303–1312.
   PubMed Web of Science ®Google Scholar
• Wu X, Ge H, Lemon B, et al. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem. 2010 Feb 19;285(8):5165–5170.
   PubMed Web of Science ®Google Scholar
• Melero S, Spirlì C, Zsembery Á, et al. Defective regulation of cholangiocyte Cl−/HCO3− and Na+/H+ exchanger activities in primary biliary cirrhosis. Hepatology. 2002 Jun;35(6):1513–1521.
   PubMed Web of Science ®Google Scholar
• Beuers U, Hohenester S, De Buy Wenniger LJM, et al. The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology. 2010 Aug 18;52(4):1489–1496.
   PubMed Web of Science ®Google Scholar
• Salas JT, Banales JM, Sarvide S, et al. Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology. 2008;134(5):1482–1493.
   PubMed Web of Science ®Google Scholar
• Hofmann AF, Zakko SF, Lira M, et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology (Baltimore Md). 2005 Dec;42(6):1391–1398.
   PubMed Web of Science ®Google Scholar
• Sombetzki M, Fuchs CD, Fickert P, et al. 24-Nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol. 2015 Apr;62(4):871–878.
   PubMed Web of Science ®Google Scholar
• Halilbasic E, Steinacher D, Trauner M. Nor-ursodeoxycholic acid as a novel therapeutic approach for cholestatic and metabolic liver diseases. Dig Dis. 2017;35(3):288–292.
   PubMed Web of Science ®Google Scholar
• Beuers U, Trauner M, Jansen P, et al. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015 Apr;62(1 Suppl):S25–S37.
   PubMed Web of Science ®Google Scholar
• Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology (Baltimore Md). 2013 May;57(5):1931–1941.
   PubMed Web of Science ®Google Scholar
• Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology (Baltimore Md). 2015 Aug;62(2):635–643.
   PubMed Web of Science ®Google Scholar
• Nozaki Y, Harada K, Sanzen T, et al. PPARγ ligand attenuates portal inflammation in the MRL-lpr mouse: a new strategy to restrain cholangiopathy in primary biliary cirrhosis. Med Mol Morphol. 2013 Sep;46(3):153–159.
   PubMed Web of Science ®Google Scholar
• Delerive P, Gervois P, Fruchart J-C, et al. Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators. J Biol Chem. 2000 Nov 24;275(47):36703–36707.
   PubMed Web of Science ®Google Scholar
• Hosonuma K, Sato K, Yamazaki Y, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol. 2015 Mar;110(3):423–431.
   PubMed Web of Science ®Google Scholar
• Cuperus FJC, Halilbasic E, Trauner M. Fibrate treatment for primary biliary cirrhosis. Curr Opin Gastroenterol. 2014 May;30(3):279–286.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li S, He L, et al. Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. Drug Des Devel Ther. 2015;9:2757–2766.
   PubMed Web of Science ®Google Scholar
• Patsenker E, Popov Y, Stickel F, et al. Inhibition of integrin αvβ6 on cholangiocytes blocks transforming growth factor-β activation and retards biliary fibrosis progression. Gastroenterology. 2008 Aug;135(2):660–670.
   PubMed Web of Science ®Google Scholar
• Cordell HJ, Han Y, Mells GF, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015;6.
   Web of Science ®Google Scholar