title: Taurolithocholic acid-3 sulfate impairs insulin signaling in cultured rat hepatocytes and perfused rat liver.
abstract: OBJECTIVE
  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) beta 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 Go6850 and tauroursodeoxycholate (TUDC) counteracted the suppression of insulin-induced IRbeta 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 IRbeta phosphorylation. In livers from 7 day bile duct-ligated rats PKB Ser(473) phosphorylation was decreased by about 50%.
  
  
  CONCLUSIONS
  TLCS induces insulin resistance by a PKC-dependent suppression of insulin-induced IRbeta 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.
authors.affiliation: Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Mannack
authors.forename: Dirk
authors.initials: D
authors.lastname: Graf
authors.forename: Markus M
authors.initials: MM
authors.lastname: Donner
authors.forename: Lisa
authors.initials: L
authors.lastname: Richter
authors.forename: Boris
authors.initials: B
authors.lastname: Gorg
authors.forename: Stephan
authors.initials: S
authors.lastname: Vom Dahl
authors.forename: Dieter
authors.initials: D
authors.lastname: Haussinger
authors.forename: Freimut
authors.initials: F
authors.lastname: Schliess
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D001652:Bile Ducts / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D008297:Male; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D019000:Phosphotyrosine; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D013655:Taurochenodeoxycholic Acid; D013658:Taurolithocholic Acid; C066776:taurolithocholic acid 3-sulfate; C031655:ursodoxicoltaurine