Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease

摘要 在过去的二十年里，人们越来越认识到一个长期的威胁，即非酒精性饮料。 脂肪性肝病（NAFLD），演变为非酒精性脂肪性肝炎（NASH），可进一步发展为 肝硬化和肝细胞癌（HCC）。NAFLD和NASH的治疗主要是通过尝试 营养调整，往往不成功，由于遵守和社会经济因素差。有 目前没有公认的NAFLD单药药物治疗。目前的建议是基于 我们在肝再生方面的研究发现，我们发现EGFR在控制肝再生方面具有独特的作用。 复制肝细胞脂肪变性。我们现在已经在喂食高脂肪食物的小鼠中扩展了这些研究 在饮用水中补充果糖（“快餐饮食”，FFD）。我们发现，在接受FFD的小鼠中， 同时EGFR抑制完全防止和消除肝细胞中的任何脂肪沉积。 此外，EGFR抑制逆转了FFD喂养4小时后建立的严重肝细胞脂肪变性。 个月机制的详细分析揭示了EGFR抑制对多种肿瘤的广泛影响。 与脂质代谢相关的转录因子以及随后与特定酶相关的结果 与脂质的生物合成和降解有关。当从另一方发出信号时， 肝细胞促有丝分裂受体酪氨酸激酶MET（HGF受体）被消除。这样做的目的 建议是探索这一发现的翻译应用。这将通过探索EGFR的影响来完成 在人类药理学中建立的抑制剂。此外，我们还将在EGFR与 和MET信号传导抑制对NAFLD的影响，旨在揭示EGFR独特的特异性途径 这可能揭示新的药理学方法，比抑制整个EGFR信号传导更集中， 及其潜在的不良并发症。在平行研究中，我们还将使用可用的人NAFLD/NASH 组织材料可在我们的匹兹堡肝脏研究中心（PLRC）的生物储存库中获得。这种材料将 根据PLRC获得的IRB的既定规则使用。我们将探索激活 EGFR依赖性途径，并将与NAFLD/NASH的组织学相关。的严重并发症 NAFLD向NASH的进展是纤维化的发展。我们已经发现了EGFR控制的信号传导 脂肪变性肝细胞中的分子，这些分子与肝星状细胞的活化有关， 增加胶原蛋白的产量。这些也为纤维化的选择性药理学提供机会， 将在拟议的研究中评估其相关性。

ABSTRACT In the last two decades, there has been an increased appreciation of a long-term threat, that of non-alcoholic fatty liver disease (NAFLD), evolving into non-alcoholic steatohepatitis (NASH), which can further advance into cirrhosis and hepatocellular carcinoma (HCC). Treatment of NAFLD and NASH is primarily through attempts at nutritional modification, often unsuccessful due to poor compliance and socioeconomic factors. There is currently no accepted single-agent pharmacologic treatment for NAFLD. The current proposal is based on findings from our work on liver regeneration, in which we discovered a unique role for EGFR for control of steatosis in replicating hepatocytes. We have now extended these studies in mice fed a high fat diet supplemented with fructose in the drinking water (“Fast Food Diet”, FFD). We found that in mice on FFD, concurrent EGFR inhibition completely prevented and eliminated any fat deposition in hepatocytes. Furthermore, EGFR inhibition reversed severe hepatocyte steatosis established after FFD feeding for 4 months. Detail analysis of the mechanisms revealed widespread effects of EGFR inhibition on multiple transcription factors related to lipid metabolism and subsequent consequences to specific enzymes associated with lipid biosynthesis and degradation. No such findings occur when signaling from the other of the two hepatocyte-mitogenic receptor tyrosine kinases, MET (the HGF receptor), was eliminated. The purpose of this proposal is to explore translational applications of this finding. This will be done by exploring effects of EGFR inhibitors established in human pharmacology. In addition, we will conduct parallel analysis between EGFR and MET signaling inhibition on their effects of NAFLD, aiming to uncover specific pathways unique to EGFR that may reveal new pharmacologic approaches more focused than the inhibition of the entire EGFR signaling with its potentially adverse complications. In parallel studies, we will also use available human NAFLD/NASH tissue material available in the Biorepository of our Pittsburgh Liver research Center (PLRC). This material will be used under the established rules of IRB obtained by PLRC for such studies. We will explore activation of EGFR dependent pathways and will correlate with the histology of NAFLD/NASH. A serious complication of progression of NAFLD to NASH is development of fibrosis. We have uncovered EGFR-controlled signaling molecules in steatotic hepatocytes, which have been associated with activation of hepatic stellate cells and enhanced production of collagens. These also offer opportunities for selective pharmacology for fibrosis and their relevance will be assessed in the studies proposed.