Original Paper

Taurolithocholic Acid-3 Sulfate Impairs Insulin Signaling in Cultured Rat Hepatocytes and Perfused Rat Liver
Gudrun Mannack, Dirk Graf, Markus M. Donner, Lisa Richter, Boris Görg, Stephan vom Dahl, Dieter Häussinger, Freimut Schliess

Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Düsseldorf

Address of Corresponding Author

Cell Physiol Biochem 2008;21:137-150 (DOI: 10.1159/000113756)

  Key Words

• Bile acids
• PKB
• Proteolysis
• Rapamycin
• Tauroursodeoxycholate
• Insulin Resistance
• Cell volume

  Abstract

Background/Aims: The role of bile acids for insulin resistance in cholestatic liver disease is unknown. Methods: The effect of taurolithocholic acid-3 sulfate (TLCS) on insulin signaling was studied in cultured rat hepatocytes and perfused rat liver. Results: TLCS induced insulin resistance at the level of insulin receptor (IR) Tyr(1158) phosphorylation, phosphoinositide (PI) 3-kinase activity and protein kinase (PK)B Ser(473) phosphorylation in cultured hepatocytes. Consistently, the insulin stimulation of the PI 3-kinase-dependent K⁺ uptake, hepatocyte swelling and proteolysis inhibition was blunted by TLCS in perfused rat liver. The PKC inhibitor Gö6850 and tauroursodeoxycholate (TUDC) counteracted the suppression of insulin-induced IR and PKB phosphorylation by TLCS. Rapamycin and dibutyryl-cAMP, which inhibited basal signaling via mammalian target of rapamycin (mTOR), restored insulin-induced PKB- but not IR phosphorylation. In livers from 7 day bile duct-ligated rats PKB Ser(473) phosphorylation was decreased by about 50%. Conclusion: TLCS induces insulin resistance by a PKC-dependent suppression of insulin-induced IR phosphorylation and the PI 3-kinase/PKB path. This can in part be compensated by a decrease of mTOR activity, which may release insulin-sensitive components downstream of the insulin receptor from tonic inhibition. The data suggest that retention of hydrophobic bile acids confers insulin resistance on the cholestatic liver.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Priv.-Doz. Dr. Freimut Schliess
Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie,
Hepatologie and Infektiologie, Moorenstrasse 5, 40225 Düsseldorf (Germany)
Tel. +49 211 81 18941, Fax: +49 211 81 17517
E-Mail schliess@med.uni-duesseldorf.de

  Article Information

Accepted: October 04, 2007
Published online: January 16, 2008
Number of Print Pages : 14