Mannack Gudrun, Graf Dirk, Donner Markus M, Richter Lisa, Gorg Boris, Vom Dahl Stephan, Haussinger Dieter, Schliess Freimut
Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany.
Cell Physiol Biochem. 2008;21(1-3):137-50. doi: 10.1159/000113756. Epub 2008 Jan 16.
BACKGROUND/AIMS: 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 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.
背景/目的：胆汁酸在胆汁淤积性肝病中对胰岛素抵抗的作用尚不清楚。
在培养的大鼠肝细胞和灌注的大鼠肝脏中研究了牛磺石胆酸-3-硫酸酯（TLCS）对胰岛素信号传导的影响。
在培养的肝细胞中，TLCS在胰岛素受体（IR）β酪氨酸（Tyr）（1158）磷酸化、磷酸肌醇（PI）3激酶活性和蛋白激酶（PK）B丝氨酸（Ser）（473）磷酸化水平诱导胰岛素抵抗。同样，在灌注的大鼠肝脏中，TLCS减弱了胰岛素对PI 3激酶依赖性钾（K+）摄取、肝细胞肿胀和蛋白水解抑制的刺激作用。蛋白激酶C（PKC）抑制剂Go6850和牛磺熊去氧胆酸（TUDC）抵消了TLCS对胰岛素诱导的IRβ和PKB磷酸化的抑制作用。雷帕霉素和二丁酰环磷腺苷（dibutyryl-cAMP）通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）的基础信号传导，恢复了胰岛素诱导的PKB磷酸化，但未恢复IRβ磷酸化。在7日胆管结扎大鼠的肝脏中，PKB丝氨酸（Ser）（473）磷酸化降低了约50%。
TLCS通过PKC依赖性抑制胰岛素诱导的IRβ磷酸化和PI 3激酶/PKB途径诱导胰岛素抵抗。这部分可以通过mTOR活性的降低来补偿，这可能会使胰岛素受体下游的胰岛素敏感成分从紧张性抑制中释放出来。数据表明，疏水性胆汁酸的潴留使胆汁淤积性肝脏产生胰岛素抵抗。
