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