Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth

非酒精性脂肪肝（NAFLD）是一个令人担忧的公共卫生问题，现在被认为是最严重的疾病。 西方世界常见的肝病。NAFLD患者可能发生非酒精性脂肪性肝炎 NASH是一种非酒精性脂肪性肝炎，其中许多发展为肝损伤，可发展为肝硬化。我们先前已经表明 在慢性胆汁淤积性肝病中，胆管细胞通过其细胞活化的产物， 如胰泌素（SCT），是胆管损伤和上皮下纤维化之间的关键环节， 以慢性肝胆损伤为特征。我们还证明了SCT/SR轴的激活 在动物模型胆汁淤积期间的肝纤维化和胆道损伤的进展中起关键作用 和人肝样品通过胆管细胞分泌转化生长因子-b1（TGF-b1）， 随后激活肝星状细胞（HSC）。最近的证据和我们新的初步数据 表明胆管细胞通过激活 胆管损伤/增殖和随后的肝纤维化。我们的初步数据表明，SCT/分泌素 受体（SR）轴在NAFLD/NASH动物模型和人肝脏的胆管细胞中上调 患有脂肪变性和脂肪性肝炎的样本支持SCT/SR轴在肝硬化中起关键作用的概念。 NAFLD和NASH的进展。基于这些发现，我们提出了中心假设， SCT/SR轴信号转导是介导增殖和活化促纤维化胆道表型的关键 导致肝脂肪变性和纤维化的进展， 非酒精性脂肪肝/NASH。为了验证我们的假设，提出了两个具体目标：（i）激活SCT/SR轴 刺激神经内分泌/促纤维化胆汁表型，以响应FFA诱导的胆汁损伤 通过旁分泌TGF-β 1依赖性机制触发HSC的活化;和（ii）抑制HSC的活化， SCT/SR轴和下游途径减弱激活的神经内分泌/促纤维化胆管细胞 在NAFLD/NASH的进展过程中，表型和肝脂肪变性和纤维化。完成 提出的研究将提供SCT/SR轴的激活如何促进的翻译机制， 介导神经内分泌/促纤维化胆汁表型激活的局部和全身反应， NAFLD/NASH进展过程中的肝胆脂肪变性和纤维化。

Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis (NASH) of which many develop hepatic injury that may progress to cirrhosis. We have previously shown that in chronic cholestatic liver diseases, cholangiocytes, through the products of their cellular activation such as secretin (SCT), are the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. We have also demonstrated that activation of the SCT/SR axis plays a key role in the progression of liver fibrosis and biliary damage during cholestasis in animal models and human liver samples via secretion of transforming growth factor-b1 (TGF-b1) by cholangiocytes and subsequent activation of hepatic stellate cells (HSCs). Recent evidence and our novel preliminary data indicate that cholangiocytes play a key role in the pathogenesis of NAFLD/NASH through activation of biliary damage/proliferation and subsequent liver fibrosis. Our preliminary data that the SCT/secretin receptor (SR) axis is upregulated in cholangiocytes in an animal model of NAFLD/NASH and human liver samples with steatosis and steatohepatitis support the concept that the SCT/SR axis plays a key role in the progression of NAFLD and NASH. Based upon these findings, we propose the central hypothesis that the SCT/SR axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) activation of the SCT/SR axis stimulates a neuroendocrine/profibrogenic biliary phenotype in response to FFA-induced biliary damage triggering the activation of HSCs via a paracrine TGF-b1-dependent mechanism; and (ii) inhibition of the SCT/SR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype and hepatic steatosis and fibrosis during the progression of NAFLD/NASH. Completion of the proposed studies will provide a translational mechanism of how activation of the SCT/SR axis promotes local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype and hepatobiliary steatosis and fibrosis during the progression of NAFLD/NASH.!