Bucher Brian T, Feng Xuesheng, Jeyabalan Geetha, Zhang Baochun, Shao Lifang, Guo Zhong, Geller David A
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
J Surg Res. 2007 Mar;138(1):15-21. doi: 10.1016/j.jss.2006.05.015. Epub 2006 Dec 15.
Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation.
GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IkappaB degradation and inhibiting NF-kappaB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity.
GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model.
These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.
尽管疏水性胆汁酸（例如甘氨酸结合型鹅去氧胆酸，GCDC）的蓄积被认为是导致胆汁淤积性肝功能障碍的一个重要因素，但其发病机制仍知之甚少。本研究的目的是探讨胆盐GCDC对诱导型一氧化氮合酶（iNOS）表达调控的影响，iNOS是肝脏炎症过程中的关键免疫调节因子。
GCDC显著降低细胞因子刺激的iNOS启动子活性以及iNOS的mRNA和蛋白表达。GCDC通过阻止IκB降解和抑制NF-κB DNA结合活性来降低iNOS启动子活性。为了探究iNOS在胆盐诱导的细胞凋亡中的作用，我们还检测了一氧化氮（NO）对caspase-3活性的影响。
GCDC强烈诱导caspase-3活性，外源性NO暴露和内源性NO合成均消除了这种增加。此外，腺病毒iNOS（AdiNOS）预处理减轻了大鼠胆管结扎模型中急性胆汁淤积诱导的肝损伤。
这些发现表明了一种新的信号通路，即潜在有毒的胆盐下调肝脏iNOS表达。iNOS介导的抗凋亡表型的这种阻断可能在某些肝脏疾病中具有重要意义。
