Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity

项目摘要 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)可能发展为肝脏损伤，并可能进展为肝硬变。我们已经证明了激活 在α-降钙素基因相关肽()/降钙素受体样受体(CRLRr)轴中起着关键作用 胆汁淤积动物模型中胆汁损伤诱导的胆管细胞增殖的作用。近期 有证据和我们新的初步数据表明，胆管细胞在胆囊癌的发病机制中起着关键作用。 NAFLD/NASH通过激活胆管损伤、导管反应(DR)、衰老和随后的肝脏 纤维化症。我们的初步数据显示，在动物的胆管细胞中，-cGRP/CRLR轴表达上调。 NAFLD/NASH(高脂饮食(HFD)和蛋氨酸和胆碱缺乏(MCD)肝毒性饮食)模型和 患有非酒精性脂肪肝和非酒精性脂肪肝的人肝脏样本支持降钙素基因相关肽/CRLR轴起关键作用的观点 在NAFLD和NASH表型的进展中。基于这些发现，我们建议中央 假设降钙素基因相关肽/CRLR轴信号在介导DR和激活的促纤维化胆管中起关键作用 触发HSC激活的表型，以及肝细胞中的脂肪变性促进了 NAFLD/NASH期间的肝纤维化。为了验证我们的假设，我们提出了两个具体目标：(I)HFD和MCD 肝性饮食诱导的降钙素基因相关肽/CRLR轴的激活刺激DR，胆汁衰老触发 在非酒精性脂肪肝/非酒精性脂肪肝期间随后的脂肪变性和纤维化；以及(Ii)治疗对、CGRP/CRLR轴的抑制 下游通路减弱激活的神经内分泌/促肝纤维化胆汁表型 NAFLD/NASH进展过程中的脂肪变性和纤维化。建议的研究将在CELL中进行 特异性CRLR基因敲除小鼠模型及人NAFLD/NASH胆管细胞系的体外研究 和3D有机体。在人类中，CGRP/CRLR轴和下游通路的激活将是相关的 NAFLD/NASH样本。成功完成拟议研究将提供一种翻译机制 降钙素基因相关肽/CLR轴的激活如何在糖尿病进展中介导DR和肝胆纤维化 NAFLD/NASH。我们的研究还将为NAFLD/NASH和其他疾病的新治疗方法提供见解 以胆管反应和肝胆纤维化为特征的肝病。

Project Summary 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 may develop hepatic injury that may progress to liver cirrhosis. We have shown that activation of the alpha-calcitonin gene-related peptide (CGRP)/Calcitonin receptor-like receptor (CRLR) axis plays a key role in cholangiocyte proliferation induced by biliary damage during cholestasis in animal models. 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, ductular reaction (DR), senescence, and subsequent liver fibrosis. Our preliminary data showing that the CGRP/CRLR axis is upregulated in cholangiocytes in animal models of NAFLD/NASH (high-fat diet (HFD) and methionine and choline-deficient (MCD) hepatoxic diet) and human liver samples with NAFLD and NASH support the concept that the CGRP/CRLR axis plays a key role in the progression of NAFLD and NASH phenotypes. Based upon these findings, we propose the central hypothesis that the CGRP/CRLR axis signaling is critical for mediating DR and activated profibrogenic biliary phenotype that triggers HSC activation, as well as steatosis in hepatocytes contributing to the progression of hepatic fibrosis during NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) HFD and MCD hepatoxic diet-induced activation of the CGRP/CRLR axis stimulates DR, biliary senescence triggering the subsequent steatosis and fibrosis during NAFLD/NASH; and (ii) Therapeutic inhibition of the CGRP/CRLR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype hepatic steatosis and fibrosis during the progression of NAFLD/NASH. The proposed studies will be performed in cell specific CRLR knockout mice models as well as in vitro studies in human NAFLD/NASH cholangiocytes cell lines and 3D organoids. The activation of the CGRP/CRLR axis and downstream pathways will be correlated in human samples of NAFLD/NASH. Successful completion of the proposed studies will provide a translational mechanism of how activation of the CGRP/CLR axis mediates DR and hepatobiliary fibrosis during the progression of NAFLD/NASH. Our study will also provide insight for novel therapeutic approaches for NAFLD/NASH and other liver diseases characterized by ductular reaction and hepatobiliary fibrosis.