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

基本信息

批准号：
10338190
负责人：
GEORGE K MICHALOPOULOS
金额：
$ 47.53万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10338190
关键词：
Adverse effects Affect Amphiregulin Attenuated Binding Cancer Patient Canertinib Cell membrane Cells Chronic Chronology Cirrhosis Collagen Complication DTR gene 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 Lead 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 base 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 prevent receptor response side effect stellate cell transcription factor transcriptome sequencing translational applications

项目摘要

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里，人们越来越认识到非酒精饮料这一长期威胁。脂肪肝病（NAFLD），演变为非酒精性脂肪性肝炎（NASH），进一步发展为肝硬化和肝细胞癌 (HCC) 主要通过尝试治疗 NAFLD 和 NASH。由于依从性差和社会经济因素，营养调整往往不成功。目前尚无公认的 NAFLD 单药药物治疗方案。我们在肝再生方面的研究成果，其中我们发现了 EGFR 在控制肝脏再生方面的独特作用。我们现在将这些研究扩展到高脂肪饮食的小鼠身上。在饮用水中补充果糖（“快餐饮食”，FFD）我们发现，在 FFD 小鼠中，同时抑制 EGFR 完全阻止并消除了肝细胞中的任何脂肪沉积。此外，EGFR 抑制逆转了 FFD 喂养 4 年后建立的严重肝细胞脂肪变性。详细的机制分析揭示了 EGFR 抑制对多种疾病的广泛影响。与脂质代谢相关的转录因子以及相关特定酶的后续后果当来自两者中的另一个的信号时，不会发生这样的发现。肝细胞促有丝分裂受体酪氨酸激酶 MET（HGF 受体）被消除。该提案旨在探索这一发现的转化应用，这将通过探索 EGFR 的作用来完成。此外，我们将在EGFR之间进行平行分析。和 MET 信号传导抑制对其 NAFLD 的影响，旨在揭示 EGFR 独特的特定途径这可能会揭示比抑制整个 EGFR 信号传导更集中的新药理学方法在平行研究中，我们还将使用现有的人类 NAFLD/NASH。我们的匹兹堡肝脏研究中心 (PLRC) 的生物储存库中提供了组织材料。在 PLRC 为此类研究获得的 IRB 既定规则下使用我们将探索激活。 EGFR 依赖性途径，并且与 NAFLD/NASH 的严重并发症相关。 NAFLD 进展为 NASH 是纤维化的发展过程，我们发现了 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激活有关这些也为纤维化和选择性药理学提供了机会。将在拟议的研究中评估它们的相关性。