Journal of Gastroenterology

, Volume 48, Issue 10, pp 1160–1170

Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients

  • Tatsuo Inamine
  • Shingo Higa
  • Fumie Noguchi
  • Shinji Kondo
  • Katsuhisa Omagari
  • Hiroshi Yatsuhashi
  • Kazuhiro Tsukamoto
  • Minoru Nakamura
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Patients with primary biliary cirrhosis (PBC) exhibit a variety of clinical manifestations and patterns of disease progression. The aim of this study was to identify genetic determinants of PBC progression.

Methods

A total of 52 tag single nucleotide polymorphisms (SNPs) of 11 candidate genes involved in regulating bile acid synthesis were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, -high resolution melting curve analysis, or -direct DNA sequencing in 315 Japanese patients with PBC.

Results

In this study, four tag SNPs of CYP7A1 (rs1457043, rs8192870, rs3808607, and rs3824260), two tag SNPs of HNF4A (rs6017340 and 6031587), and one SNP of PPARGC1A (rs8192678) showed a significant association with PBC progression. In addition, a dual luciferase assay revealed that the polymorphism of rs3808607 in CYP7A1 altered the expression of CYP7A1 in HepG2. Specifically, the CYP7A1 promoter carrying the risk G allele for PBC progression induced higher expression of CYP7A1 under both the normal and cholestatic conditions in vitro as compared to another promoter carrying the non-risk T allele.

Conclusion

These results suggested that the genetic variants of CYP7A1 and its transcriptional activators (HNF4A and PPARGC1A) may activate bile acid synthesis, resulting in the accumulation of bile acids in hepatocytes and eventually leading to the predisposition to PBC progression. Thus, the regulation of CYP7A1 expression may represent an attractive therapeutic target for cholestatic liver diseases including PBC.

Keywords

PBC progression Bile acid synthesis CYP7A1 PGC-1α HNF4α 

Supplementary material

535_2012_730_MOESM1_ESM.doc (171 kb)
Supplementary material 1 (DOC 171 kb)

References

  1. 1.
    Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev. 2000;174:210–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Kaplan MM, Gershwin ME. Primary biliary cirrhosis. New Engl J Med. 2005;353:1261–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52:745–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Invernizzi P, Selmi C, Poli F, Frison S, Floreani A, Alvaro D, et al. Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: a multicenter study of 664 patients and 1992 healthy controls. Hepatology. 2008;48:1906–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. New Engl J Med. 2009;360:2544–55.PubMedCrossRefGoogle Scholar
  6. 6.
    Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, et al. Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): the HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. Hepatol Res. 2010;40:494–504.PubMedCrossRefGoogle Scholar
  7. 7.
    Poupon R, Ping C, Chrétien Y, Corpechot C, Chazouillères O, Simon T, et al. Genetic factors of susceptibility and of severity in primary biliary cirrhosis. J Hepatol. 2008;49:1038–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Juran BD, Atkinson EJ, Schlicht EM, Fridley BL, Lazaridis KN. Primary biliary cirrhosis is associated with a genetic variant in the 3′ flanking region of the CTLA4 gene. Gastroenterology. 2008;135:1200–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Joshita S, Umemura T, Yoshizawa K, Katsuyama Y, Tanaka E, Nakamura M, et al. Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol. 2010;53:537–41.PubMedCrossRefGoogle Scholar
  10. 10.
    Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42:658–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010;42:655–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Hirschfield GM, Gershwin ME. Primary biliary cirrhosis: one disease with many faces. Isr Med Assoc J. 2011;13:55–9.PubMedGoogle Scholar
  13. 13.
    Aiba Y, Nakamura M, Joshita S, Inamine T, Komori A, Yoshizawa K, et al. Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients. J Gastroenterol. 2011;46:1203–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA. Sánchez Pozzi EJ. Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications. Clin Sci. 2011;121:523–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Eloranta JJ, Kullak-Ublick GA. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism. Arch Biochem Biophys. 2005;433:397–412.PubMedCrossRefGoogle Scholar
  16. 16.
    Chiang JY. Bile acids: regulation of synthesis. J Lipid Res. 2009;50:1955–66.PubMedCrossRefGoogle Scholar
  17. 17.
    De Fabiani E, Mitro N, Gilardi F, Caruso D, Galli G, Crestani M. Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle. J Biol Chem. 2003;278:39124–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Li T, Kong X, Owsley E, Ellis E, Strom S, Chiang JY. Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c. J Biol Chem. 2006;281:28745–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, et al. Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int. 2007;27:920–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Takeyama Y, Kanegae K, Inomata S, Takata K, Tanaka T, Ueda S, et al. Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7α-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis. Med Mol Morphol. 2010;43:134–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, et al. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol. 2006;290:G923–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology. 2009;50:291–308.PubMedCrossRefGoogle Scholar
  23. 23.
    Scheuer P. Primary biliary cirrhosis. Proc R Soc Med. 1967;60:1257–60.PubMedGoogle Scholar
  24. 24.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Song CM, Yeo BH, Tantoso E, Yang Y, Lim YP, Li KB, et al. iHAP—integrated haplotype analysis pipeline for characterizing the haplotype structure of genes. BMC Bioinforma. 2006;7:525.CrossRefGoogle Scholar
  26. 26.
    Choi Y-S, Hong J-M, Lim S, Ko KS, Pak YK. Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter. Biochem Biophys Res Commun. 2006;344:708–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, et al. A Klotho α variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea. Gastroenterology. 2011;140:1934–42.PubMedCrossRefGoogle Scholar
  28. 28.
    Inamine T, Nakamura M, Kawauchi A, Shirakawa Y, Hashiguchi H, Aiba Y, et al. A polymorphism in the integrin α V subunit gene affects the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol. 2011;46:676–86.PubMedCrossRefGoogle Scholar
  29. 29.
    De Castro-Orós I, Pampín S, Cofán M, Mozas P, Pintó X, Salas-Salvadó J, et al. Promoter variant -204A>C of the cholesterol 7α -hydroxylase gene: association with response to plant sterols in humans and increased transcriptional activity in transfected HepG2 cells. Clin Nutr. 2011;30:239–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Lu Y, Feskens EJ, Boer JM, Müller M. The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population. Atherosclerosis. 2010;210:14–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009;49:1228–35.PubMedCrossRefGoogle Scholar
  32. 32.
    Perez M-JJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677–89.PubMedCrossRefGoogle Scholar
  33. 33.
    Puigserver P, Spiegelman BM. Peroxisome Proliferator-Activated Receptor-gamma Coactivator 1alpha (PGC-1alpha): transcriptional Coactivator and Metabolic Regulator. Endocr Rev. 2003;24:78–90.PubMedCrossRefGoogle Scholar
  34. 34.
    Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009;156:7–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2012

Authors and Affiliations

  • Tatsuo Inamine
    • 1
  • Shingo Higa
    • 1
  • Fumie Noguchi
    • 1
  • Shinji Kondo
    • 1
  • Katsuhisa Omagari
    • 2
  • Hiroshi Yatsuhashi
    • 3
  • Kazuhiro Tsukamoto
    • 1
  • Minoru Nakamura
    • 3
    • 4
  1. 1.Department of PharmacotherapeuticsNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  2. 2.Department of Nutrition, Faculty of Nursing and NutritionSiebold University of NagasakiNagasakiJapan
  3. 3.Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Department of HepatologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  4. 4.Headquarters of PBC Research in the NHO Study Group for Liver Disease in Japan (NHOSLJ)NagasakiJapan

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