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Digestive Diseases and Sciences

, Volume 50, Issue 3, pp 514–524 | Cite as

A Nuclear Receptor Ligand Down-Regulates Cytosolic Phospholipase A 2 Expression to Reduce Bile Acid–Induced Cyclooxygenase 2 Activity in Cholangiocytes: Implications of Anticarcinogenic Action of Farnesoid X Receptor Agonists

  • Daisuke Komichi
  • Susumu TazumaEmail author
  • Tomoji Nishioka
  • Hideyuki Hyogo
  • Kazuaki Chayama
Article

Abstract

Bile acids are considered to be involved in the development of biliary tract carcinoma, although the underlying mechanisms are yet to be established. The aims of this study were (1) to investigate the carcinogenic role of bile acids in the biliary system based on the arachidonate–prostanoid pathway and (2) to clarify the therapeutic role of a farnesoid X receptor (FXR) ligand that modifies bile acid metabolism. Immortalized mouse cholangiocytes were incubated with glycochenodeoxycholate (GCDC), taurocholate, taurochenodeoxycholate, taurodeoxycholate, and tauroursodeoxycholate. GCDC induced cyclooxygenase 2 (COX-2) expression (Western blotting, 1.7-fold; RT-PCR, 2.3-fold) and prostaglandin (PG) production (PGE2, 6.3-fold; PGF, 8.5-fold), whereas cytosolic phospholipase A2 (cPLA2) expression and activity were reduced. In contrast, no marked changes were induced by the other bile acids. When the same experiment was performed in the presence of a synthetic FXR ligand (GW4064), cPLA2 expression and activity were reduced, although COX-2 expression was unchanged. GW4064 also suppressed PG generation by 40%. In conclusion, the present findings suggest a carcinogenic potential of GCDC. A synthetic FXR ligand (GW4064) inhibited the induction of COX-2 activity (detected as PG production) by GCDC, suggesting its anticarcinogenic potential. This effect seemed to be due to down-regulation of cPLA2. FXR ligands may have therapeutic potential against biliary carcinogenesis, but a delivery system for these agents is still to be developed.

Keywords:

cytoprotection glycochenodeoxycholate GW4064 prostaglandin. 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Daisuke Komichi
    • 1
  • Susumu Tazuma
    • 1
    • 2
    • 3
    Email author
  • Tomoji Nishioka
    • 1
  • Hideyuki Hyogo
    • 1
    • 2
  • Kazuaki Chayama
    • 1
  1. 1.Departments of Medicine and Molecular ScienceHiroshima UniversityHiroshimaJapan
  2. 2.Departments of General Medicine and Clinical Pharmacotherapy, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  3. 3.Department of General Medicine and Clinical Pharmacotherapy, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan

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