Insulin inhibits secretin-induced ductal secretion by... : Hepatology (original) (raw)

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Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKA activity

LeSage, Gene D.1, 2; Marucci, Luca3; Alvaro, Domenico4; Glaser, Shannon S.1; Benedetti, Antonio3; Marzioni, Marco5; Patel, Tushar1; Francis, Heather1; Phinizy, Jo Lynne1; Alpini, Gianfranco*,1,5,6

1Departments of Internal Medicine, Scott & White Hospital and The Texas A&M University System HSC COM, Temple, TX

2Medical Biochemistry and Genetics, Scott & White Hospital and The Texas A&M University System HSC COM, Temple, TX

3Department of Gastroenterology, University of Ancona, Ancona, Italy

4Division of Gastroenterology, University of Rome, “La Sapienza,” Rome, Italy

5Medical Physiology, Scott & White Hospital and The Texas A&M University System HSC COM, Temple, TX

6Central Texas Veterans Health Care System, Temple, TX

E-mail:[email protected]; [email protected]

*Address reprint requests to: 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. hyphen;28871, Alcalá de Henares, Spain. fax: 254-724-5944 and 254-742-7145.

Received April 19, 2002; Accepted June 20, 2002; previously published online December 30, 2003

Abstract

Insulin stimulates canalicular bile flow by interaction with hepatocytes. Insulin regulates the function of a number of epithelia through activation and membrane translocation of Ca2+-dependent PKC isoforms. No information exists regarding insulin regulation of ductal bile secretion. The aim of the study was to determine the role and mechanisms of action of insulin in the regulation of cholangiocyte secretion in BDL rats. We determined the subcellular localization of insulin receptor in cholangiocytes. We measured the effect of insulin on (1) secretin-stimulated cAMP levels in cholangiocytes and duct expansion in intrahepatic bile duct units (IBDUs) in the absence or presence of BAPTA/AM, H7 or rottlerin and (2) bile flow. We evaluated (1) if insulin effects are associated with activation of PKC alpha and (2) if activation of PKC causes inhibition of secretin-stimulated cAMP levels and PKA activity. We found insulin receptors only in the apical domain of cholangiocytes. Insulin inhibited secretin-induced choleresis and secretin-stimulated cholangiocyte cAMP levels. Insulin inhibited secretin-induced secretion in IBDUs when applied at the basolateral membrane or microinjected into IBDU lumen. Insulin inhibitory effects on cholangiocyte secretion were blocked by BAPTA/AM and H7. Insulin induced activation of PKC alpha, which decreased secretin-stimulated cAMP and PKA activity. In conclusion, insulin inhibited secretin-induced ductal secretion of BDL rats through activation of PKC and inhibition of secretin-stimulated cAMP and PKA activity. In conclusion, insulin counter-regulates cholangiocyte secretory processes in the BDL model, which is characterized by cholangiocyte proliferation.