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.

摘要 在过去的二十年里，人们越来越认识到一种长期的威胁，那就是非酒精 脂肪肝(NAFLD)，演变为非酒精性脂肪性肝炎(NASH)，可进一步发展为 肝硬变和肝细胞癌。NAFLD和NASH的治疗主要通过尝试 营养改良，往往由于依从性差和社会经济因素而不成功。的确有 目前，NAFLD尚无公认的单一药物治疗方法。目前的提案是基于 我们在肝再生方面的研究结果，在这项工作中，我们发现EGFR在控制 复制肝细胞中的脂肪变性。我们现在已经将这些研究扩展到喂食高脂肪食物的小鼠身上 在饮用水中添加果糖(“快餐饮食”，FFD)。我们发现，在FFD的小鼠身上， 同时抑制EGFR可完全防止和消除肝细胞中的任何脂肪沉积。 此外，抑制EGFR可逆转FFD喂养4周后形成的严重肝细胞脂肪变性。 月份。对机制的详细分析揭示了EGFR抑制对多发性硬化的广泛影响。 与脂代谢相关的转录因子及其对特定酶的后续影响 与脂肪的生物合成和降解有关。当从两者中的另一个发信号时，不会出现这样的发现 肝细胞有丝分裂受体酪氨酸激酶，MET(肝细胞生长因子受体)被消除。这样做的目的是 建议是探索这一发现的翻译应用。这将通过探索EGFR的影响来实现 在人类药理学中确立的抑制剂。此外，我们将对EGFR进行平行分析 Met信号抑制NAFLD的作用，旨在发现EGFR特有的特定通路 这可能揭示出比抑制整个EGFR信号更有针对性的新的药理学方法 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类NAFLD/NASH 我们匹兹堡肝脏研究中心(PLRC)的生物库中提供了组织材料。这份材料将 根据公共研究中心获得的内部审查委员会的既定规则用于此类研究。我们将探索激活 EGFR依赖通路，并将与NAFLD/NASH的组织学相关。严重的并发症 NAFLD向NASH的进展是纤维化的发展。我们发现了EGFR控制的信号 脂肪变性肝细胞中的分子，与肝星状细胞的激活和 提高了胶原蛋白的产量。这些也提供了选择性药理学治疗纤维化和 它们的相关性将在拟议的研究中进行评估。