Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats

Authors

  • Anastasia Renzi,

    1. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University “Sapienza,” Rome, Italy
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  • Sharon DeMorrow,

    1. Scott & White Digestive Disease Research Center, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Paolo Onori,

    1. Department of Biotechnological and Applied Clinical Sciences, State University of L'Aquila, L'Aquila, Italy
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  • Guido Carpino,

    1. Department of Health Sciences, University of Rome “Foro Italico,” Rome, Italy
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  • Romina Mancinelli,

    1. Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University “Sapienza,” Rome, Italy
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  • Fanyin Meng,

    1. Scott & White Digestive Disease Research Center, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    3. Division of Research and Education, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Julie Venter,

    1. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Mellanie White,

    1. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Antonio Franchitto,

    1. Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University “Sapienza,” Rome, Italy
    2. Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy
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  • Heather Francis,

    1. Scott & White Digestive Disease Research Center, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    3. Division of Research and Education, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Yuyan Han,

    1. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Yoshiyuki Ueno,

    1. Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
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  • Giuseppina Dusio,

    1. Division of Research and Education, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Kendal J. Jensen,

    1. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • John J. Greene Jr.,

    1. Pathology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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  • Shannon Glaser,

    1. Division of Research, Central Texas Veterans Health Care System, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Scott & White Digestive Disease Research Center, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    3. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
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    • Drs. Alpini, Glaser and Gaudio share the last authorship.

  • Eugenio Gaudio,

    1. Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University “Sapienza,” Rome, Italy
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    • Drs. Alpini, Glaser and Gaudio share the last authorship.

  • Gianfranco Alpini

    Corresponding author
    1. Division of Research, Central Texas Veterans Health Care System, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    2. Scott & White Digestive Disease Research Center, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    3. Department of Medicine, Division of Gastroenterology, Scott & White Healthcare and Texas A&M Health Science Center, College of Medicine, Temple, TX
    • Ph.D., Scott & White Digestive Diseases Research Center, Central Texas Veterans Health Care System, Texas A & M Health Science Center College of Medicine, Olin E. Teague Medical Center, 1901 South 1st Street, Building 205, 1R60, Temple, TX 76504
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    • Drs. Alpini, Glaser and Gaudio share the last authorship.

    • fax: 743-0378 or 743-0555


  • Potential conflict of interest: Nothing to report.

Abstract

Secretin stimulates ductal secretion by interacting with secretin receptor (SR) activating cyclic adenosine 3′,5′-monophosphate/cystic fibrosis transmembrane conductance regulator/chloride bicarbonate anion exchanger 2 (cAMP⇒CFTR⇒Cl/HCOmath image AE2) signaling that is elevated by biliary hyperplasia. Cholangiocytes secrete several neuroendocrine factors regulating biliary functions by autocrine mechanisms. Melatonin inhibits biliary growth and secretin-stimulated choleresis in cholestatic bile-duct–ligated (BDL) rats by interaction with melatonin type 1 (MT1) receptor through down-regulation of cAMP-dependent signaling. No data exist regarding the role of melatonin synthesized locally by cholangiocytes in the autocrine regulation of biliary growth and function. In this study, we evaluated the (1) expression of arylalkylamine N-acetyltransferase (AANAT; the rate-limiting enzyme for melatonin synthesis from serotonin) in cholangiocytes and (2) effect of local modulation of biliary AANAT expression on the autocrine proliferative/secretory responses of cholangiocytes. In the liver, cholangiocytes (and, to a lesser extent, BDL hepatocytes) expressed AANAT. AANAT expression and melatonin secretion (1) increased in BDL, compared to normal rats and BDL rats treated with melatonin, and (2) decreased in normal and BDL rats treated with AANAT Vivo-Morpholino, compared to controls. The decrease in AANAT expression, and subsequent lower melatonin secretion by cholangiocytes, was associated with increased biliary proliferation and increased SR, CFTR, and Cl/HCOmath image AE2 expression. Overexpression of AANAT in cholangiocyte cell lines decreased the basal proliferative rate and expression of SR, CFTR, and Cl/HCOmath image AE2 and ablated secretin-stimulated biliary secretion in these cells. Conclusion: Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013)

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