Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms
Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms
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Tauroursodeoxycholate 通过 β1-整合素和蛋白激酶 A 依赖性机制保护大鼠肝细胞免受胆汁酸诱导的细胞凋亡
DOI：
10.1159/000430262
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发表时间：
2015
影响因子：
--
通讯作者：
Häussinger D
中科院分区：
文献类型：
--
作者：
Sommerfeld A;Reinehr R;Häussinger D
超脱氧胆酸在体内可迅速转化为牛磺酸缀合物，常用于治疗胆汁淤积性肝病。除了胆甾作用外，牛磺酸脱氧胆酸盐（TUDC）还可以保护肝细胞免受胆汁酸诱导的凋亡，但其抗凋亡作用的机制尚不清楚。方法采用灌注大鼠肝脏和离体大鼠肝细胞研究其作用机制。结果TUDC在CD95与表皮生长因子受体相关的水平上抑制GCDC诱导的CD95死亡受体的激活。这是由于tudc快速诱导β 1-整合素依赖性环AMP （cAMP）信号，诱导双特异性丝裂原活化蛋白（MAP）激酶磷酸酶1 (MKP-1)，阻止gcd诱导的丝裂原活化蛋白激酶激酶4 （MKK4）磷酸化和c-jun- nh2末端激酶（JNK）活化。此外，TUDC诱导了蛋白激酶a （PKA）介导的CD95丝氨酸/苏氨酸磷酸化，这是CD95的内化信号。此外，TUDC以β 1-整合素和pka依赖的方式抑制gcdc诱导的CD95靶向质膜。与此相一致的是，牛磺胆酸钠共转运多肽（Ntcp）转染的HepG2细胞中β 1-整合素siRNA的敲低可消除TUDC对gcd诱导的凋亡的保护作用。结论tudc通过β 1-整合素介导的cAMP的形成发挥其抗凋亡作用，cAMP可在JNK激活和CD95丝氨酸/苏氨酸磷酸化水平上阻止疏水胆汁酸活化CD95。
Background/AimsUrsodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC) can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood.MethodsThese mechanisms were investigated in perfused rat liver and isolated rat hepatocytes.ResultsIt was found that TUDC inhibited the glycochenodeoxycholate (GCDC)-induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC-induced β 1-integrin-dependent cyclic AMP (cAMP) signal with induction of the dual specificity mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1), which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4) and c-jun-NH 2-terminal kinase (JNK) activation. Furthermore, TUDC induced a protein kinase A (PKA)-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a β 1-integrin-and PKA-dependent manner. In line with this, the β 1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp)-transfected HepG2 cells abolished the protective effect of TUDC against GCDC-induced apoptosis.ConclusionTUDC exerts its anti-apoptotic effect via a β 1-integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation.
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178 胆盐诱导的肝细胞凋亡涉及体外和体内表皮生长因子受体依赖性 CD95-酪氨酸磷酸化
DOI：
--
发表时间：
2003
期刊：
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
--
发表时间：
2003
期刊：
影响因子：
--
作者：
R. Reinehr;F. Schliess;D. Haeussinger
通讯作者：
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影响因子：
29.4
作者：
F. Schliess;A. Kurz;D. Häussinger
通讯作者：
D. Häussinger
DOI：
--
发表时间：
2010
期刊：
--
影响因子：
--
作者：
Haixia Gong;Bo Shen;P. Flevaris;Christina R. Chow;S. Lam;T. Voyno-Yasenetskaya;T. Kozasa;Xiaoping Du
通讯作者：
Haixia Gong;Bo Shen;P. Flevaris;Christina R. Chow;S. Lam;T. Voyno-Yasenetskaya;T. Kozasa;Xiaoping Du