Autoimmune, Cholestatic and Biliary Disease

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Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice†‡§

  1. Emina Halilbasic1,
  2. Romina Fiorotto2,
  3. Peter Fickert1,
  4. Hanns-Ulrich Marschall3,
  5. Tarek Moustafa1,
  6. Carlo Spirli2,
  7. Andrea Fuchsbichler4,
  8. Judith Gumhold1,
  9. Dagmar Silbert1,
  10. Kurt Zatloukal4,
  11. Cord Langner4,
  12. Uday Maitra5,
  13. Helmut Denk4,
  14. Alan F. Hofmann6,
  15. Mario Strazzabosco2,7,8,
  16. Michael Trauner1,*

Article first published online: 8 FEB 2009

DOI: 10.1002/hep.22891

Issue

Hepatology

Hepatology

Volume 49, Issue 6, pages 1972–1981, June 2009

Additional Information

How to Cite

Halilbasic, E., Fiorotto, R., Fickert, P., Marschall, H.-U., Moustafa, T., Spirli, C., Fuchsbichler, A., Gumhold, J., Silbert, D., Zatloukal, K., Langner, C., Maitra, U., Denk, H., Hofmann, A. F., Strazzabosco, M. and Trauner, M. (2009), Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice. Hepatology, 49: 1972–1981. doi: 10.1002/hep.22891

Author Information

  1. 1

    Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine, Medical University of Graz, Graz, Austria

  2. 2

    Section of Digestive Diseases, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT

  3. 3

    Karolinska University Hospital Huddinge, Stockholm, Sweden

  4. 4

    Institute of Pathology, Medical University of Graz, Graz, Austria

  5. 5

    Department of Organic Chemistry, Indian Institute of Science, Bangalore, India

  6. 6

    Department of Medicine, University of California, San Diego, CA

  7. 7

    CeLiveR, Ospedali Riuniti di Bergamo, Bergamo, Italy

  8. 8

    Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milan, Italy

*Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, Medical University Graz, Auenbruggerplatz 16, 8036 Graz, Austria

  1. †

    See Editorial on Page 1795

  2. ‡

    Potential conflict of interest: Nothing to report.

  3. §

    The Medical University of Graz has filed the patent for the use of norUDCA in the treatment of liver diseases, and Michael Trauner, Alan Hofmann, and Peter Fickert are listed as inventors (publication number WO2006119803).

Publication History

  1. Issue published online: 28 MAY 2009
  2. Article first published online: 8 FEB 2009
  3. Accepted manuscript online: 8 FEB 2009 12:00AM EST
  4. Manuscript Accepted: 26 JAN 2009
  5. Manuscript Received: 18 SEP 2008

Funded by

  • Austrian Science Foundation. Grant Number: P19118-B05
  • GEN-AU project. Grant Number: GZ 200.139/1-VI/1/2006
  • Austrian Ministry for Science
  • Swedish Research Council
  • The Swedish Medical Association
  • Ph.D. program of the Medical University of Graz
  • Fondazione S. Martino, Bergamo
  • National Institutes of Health. Grant Numbers: DK079005, DK64891
  • Yale University Liver Center (National Institutes of Health). Grant Number: DK34989
  • Cystic Fibrosis Foundation. Grant Number: CFF-FIOROT0810
  • ALF/AASLD Liver Scholar Award
  • JNCASR, Bangalore

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Abstract

24-norursodeoxycholic acid (norUDCA), a side chain–modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2−/− mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr−/− mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO3− -output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO3− -dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO 3− -output also in Cftr−/− mice. In Mdr2−/− mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA. Conclusion:The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO3− -rich hypercholeresis that protects the liver from cholestatic injury. (HEPATOLOGY 2009;49:1972–1981.)

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