Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth

非酒精性脂肪性肝病(NAFLD)是一个令人担忧的公共卫生问题，目前被认为是最严重的 西方世界常见的肝病。非酒精性脂肪肝患者可能发展为非酒精性脂肪性肝炎 (NASH)，其中许多人发生肝损伤，可能进展为肝硬变。我们之前已经展示了 在慢性淤胆性肝病中，胆管细胞通过其细胞激活的产物 如分泌素(SCT)，是胆管损伤和上皮下纤维化之间的关键环节。 是慢性肝胆损伤的特征。我们还证明了SCT/SR轴的激活 在胆汁淤积的动物模型中，在肝纤维化和胆管损伤的进展中起关键作用 和人肝标本通过胆管细胞分泌转化生长因子-β1(TGF-β1)和 随后激活肝星状细胞(HSCs)。最近的证据和我们新的初步数据 提示胆管细胞在NAFLD/NASH的发病机制中起关键作用。 胆管损伤/增殖和随后的肝纤维化。我们的初步数据显示，SCT/分泌素 NAFLD/NASH和人肝胆管细胞受体(SR)轴上调 脂肪变性和脂肪性肝炎的样本支持SCT/SR轴在 NAFLD和NASH的进展。基于这些发现，我们提出了中心假设，即 SCT/SR轴信号转导通路在介导增殖和活化的促纤维化胆管表型中的关键作用 这在肝脂肪变性和肝纤维化的发病机制中起着重要作用。 NAFLD/NASH。为了验证我们的假设，我们提出了两个具体的目标：(I)激活SCT/SR轴 刺激神经内分泌/促纤维化胆管表型对FFA诱导的胆管损伤的反应 通过旁分泌的转化生长因子-β1依赖的机制触发肝星状细胞的激活；以及(Ii)抑制 NAFLD/NASH进展过程中的表型和肝脏脂肪变性及纤维化。已完成的 拟议的研究将提供SCT/SR轴激活如何促进的翻译机制 局部和全身反应介导神经内分泌/促纤维生成胆管表型和 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.!