Taurolithocholic acid-3 sulfate impairs insulin signaling in cultured rat hepatocytes and perfused rat liver.
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.
Mannack
Gudrun
G
Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
Graf
Dirk
D
Donner
Markus M
MM
Richter
Lisa
L
Gorg
Boris
B
Vom Dahl
Stephan
S
Haussinger
Dieter
D
Schliess
Freimut
F
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
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