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

抑制 EGF 受体可预防和逆转非酒精性脂肪肝

• 批准号: 10552658
• 负责人: Bharat Bhushan
• 金额: $ 48.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552658
• 关键词: Adverse effects; Affect; Amphiregulin; Attenuated; Binding; Cancer Patient; Canertinib; Cell membrane; Cells; Chronic; Chronology; Cirrhosis; Collagen; Complication; Deposition; Development; Diet; Dose; Down-Regulation; EGF gene; EGFR inhibition; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exposure to; Family; Fatty Liver; Fatty acid glycerol esters; Female; Fibrosis; Freezing; Fructose; Funding; Gene Expression Profile; Glucose; Heparin Binding; Hepatic; Hepatic Stellate Cell; Hepatocyte; Hepatology; Hepatotoxicity; High Fat Diet; Histology; Human; Inflammation; Institutional Review Boards; Knockout Mice; Ligands; Lipids; Liver; Liver Regeneration; MET gene; Malignant neoplasm of liver; Manuscripts; Metabolism; MicroRNAs; Modification; Mus; Nutritional; Paraffin Embedding; Pathway Analysis; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Phosphorylation; Phosphotransferases; Population; Predictive Factor; Primary carcinoma of the liver cells; Process; Production; Proteins; Publishing; RNA; Receptor Protein-Tyrosine Kinases; Regulatory Pathway; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Socioeconomic Factors; Therapeutic; Time; Tissues; Toxic effect; United States National Institutes of Health; Up-Regulation; Western World; Work; biobank; design; drinking water; fast food; feeding; gender difference; human subject; human tissue; inhibitor; integrin-linked kinase; lipid biosynthesis; lipid metabolism; male; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; pharmacologic; prevent; receptor; response; side effect; stellate cell; transcription factor; transcriptome sequencing; translational applications

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.

抽象的 在过去的二十年中，人们对长期威胁的欣赏是非酒精的威胁 脂肪肝病（NAFLD），演变成非酒精性脂肪性肝炎（NASH），可以进一步发展为 肝硬化和肝细胞癌（HCC）。 NAFLD和NASH的处理主要是通过尝试 营养修饰，由于依从性和社会经济因素不佳而经常失败。有 目前尚未接受NAFLD的接受单药物治疗。当前的提议基于 从我们在肝脏再生方面的工作中的发现，我们在其中发现了EGFR的独特作用 在复制肝细胞时进行脂肪变性。我们现在已经扩展了在喂养高脂饮食的小鼠中的这些研究 补充饮用水中的果糖（“快餐饮食”，FFD）。我们发现在FFD的小鼠中， 同时进行的EGFR抑制完全阻止了肝细胞中的任何脂肪沉积。 此外，EGFR抑制作用逆转了FFD喂养后建立的严重肝细胞脂肪变性4 月份。该机制的详细分析揭示了EGFR抑制对多重的宽度影响 转录因子与脂质代谢以及随后与相关酶的后果有关 脂质生物合成和降解。当两者中的另一个发出信号时，没有发生这样的发现 消除了Met（HGF受体）的肝细胞有线受体酪氨酸激酶。这个目的 建议是探索这一发现的翻译应用。这将通过探索EGFR的效果来完成 在人类药理学中建立的抑制剂。此外，我们将在EGFR之间进行并行分析 并满足信号传导对NAFLD影响的抑制，旨在发现EGFR独有的特定途径 这可能揭示了与抑制整个EGFR信号的抑制更为集中的新药理方法 具有潜在的不良并发症。在平行研究中，我们还将使用可用的人类NAFLD/NASH 组织材料可在我们的匹兹堡肝脏研究中心（PLRC）的生物库中提供。该材料会 根据PLRC获得的IRB规则用于此类研究。我们将探索激活 EGFR依赖性途径，将与NAFLD/NASH的组织学相关。严重的并发症 NAFLD向NASH的发展是纤维化的发展。我们发现了EGFR控制的信号传导 脂肪性肝细胞中的分子，与肝星状细胞的激活有关 增强的胶原蛋白产生。这些还为纤维化选择性药理学提供了机会 他们的相关性将在提出的研究中进行评估。