Taurolithocholic acid-3 sulfate impairs insulin signaling in cultured rat hepatocytes and perfused rat liver

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
Gudrun MannackFreimut Schliess

Abstract

The role of bile acids for insulin resistance in cholestatic liver disease is unknown. The effect of taurolithocholic acid-3 sulfate (TLCS) on insulin signaling was studied in cultured rat hepatocytes and perfused rat liver. 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%. 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 insul...Continue Reading

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