Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha

Authors

  • Gianfranco Alpini,

    Corresponding author
    1. Department of Internal Medicine, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
    2. Medical Physiology, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
    3. Central Texas Veterans Health Care System, Temple, TX
    • Associate Professor of Internal Medicine and Medical Physiology, The Texas A&M University System, HSC COM and Central Texas Veterans HCS, MRB, 702 South West H.K. Dodgen Loop, Temple, TX 76504. fax: 254-724-5944 and 254-742-7145.
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  • Leonardo Baiocchi,

    1. Medical Physiology, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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  • Shannon Glaser,

    1. Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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  • Yoshiyuki Ueno,

    1. Department of Internal Medicine, Tohoku University School of Medicine, Aobaku, Sendai, Japan
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  • Marco Marzioni,

    1. Medical Physiology, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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  • Heather Francis,

    1. Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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  • Jo Lynne Phinizy,

    1. Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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  • Mario Angelico,

    1. Chair of Gastroenterology, Dept. of Public Health, University of Rome Tor Vergata, Rome, Italy
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  • Gene LeSage

    1. Department of Internal Medicine, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
    2. Medical Biochemistry and Genetics, White Hospital and The Texas A&M University System Health Science Center, College of Medicine, Temple, TX
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Abstract

Accumulating bile acids (BA) trigger cholangiocyte proliferation in chronic cholestasis. The aim of this study was to determine if ursodeoxycholate (UDCA) or tauroursodeoxycholate (TUDCA) chronic feeding prevents the increased cholangiocyte growth and secretion in bile duct–ligated (BDL) rats, if UDCA and TUDCA effects are associated with increased cholangiocyte apoptosis, and to determine if this inhibition is dependent on increased intracellular Ca2+ ([Ca2+]i) and activation of protein kinase C (PKC) alpha. Immediately after BDL, rats were fed UDCA or TUDCA (both 275 μmol/d) for 1 week. We determined the number of bile ducts in liver sections, cholangiocyte proliferation (by measurement of H3 histone and proliferating cellular nuclear antigen in isolated cholangiocytes), and ductal secretion. In purified cholangiocytes from 1-week BDL rats, we evaluated if UDCA and TUDCA directly inhibit cholangiocyte proliferation and secretin-stimulated adenosine 3', 5'-monophosphate levels. We determined if UDCA and TUDCA activate PKC, increase [Ca2+]i, and alter the apical BA transporter (ABAT) expression in cholangiocytes. UDCA and TUDCA inhibited in vivo the cholangiocyte proliferation, secretion, and ABAT expression. In vitro UDCA and TUDCA inhibition of cholangiocyte growth and secretion required increased [Ca2+]i and PKC alpha. In conclusion, activation of Ca2+-dependent PKC alpha is required for UDCA and TUDCA inhibition of cholangiocyte growth and secretion. Reduced cholangiocyte ABAT may decrease endogenous BA stimulation of cholangiocyte growth and secretion.

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