Role and Mechanisms of E4BP4 over-activation in diet-induced fatty liver disease

E4BP4过度激活在饮食诱导的脂肪肝中的作用和机制

基本信息

批准号：
9913312
负责人：
Xin Tong
金额：
$ 41.18万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-10 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913312
关键词：
ADD-1 protein Acute Adult Affect Apoptosis Automobile Driving Binding Proteins Cholesterol Chronic Cirrhosis Clinical Research Cultured Cells DNA Binding Data Diet Disease Disease Progression Failure Fatty Liver Fatty acid glycerol esters Fibrosis Fructose General Population Hepatic Hepatocyte High Fat Diet Inflammation Insulin Knock-out Knockout Mice Knowledge Light Lipid A Lipids Liver Liver Failure Liver diseases Measures Mediator of activation protein Messenger RNA Molecular Monitor Mus Nuclear Nutritional Obesity Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Population Prevention Preventive Regulation Reporting Role Stress Testing Therapeutic Time Transcription Repressor Triglycerides base chronic liver disease effective therapy endoplasmic reticulum stress feeding lipid biosynthesis lipid metabolism liver inflammation liver transplantation mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics overexpression prevent promoter response transcription factor

项目摘要

Non-alcoholic liver disease (NAFLD) is the most common liver disease, afflicting 30% of the general population. So far, there has been no effective treatment for NAFDL. Approximately 10% of patients with NAFLD progress from simple steatosis to non-alcoholic steatohepatitis (NASH) and eventually live failure. For patients of NAFLD with liver failure, liver transplant is the only therapeutic option. In spite of a strong correlation between diets rich in fat, cholesterol, and fructose and NAFLD, molecular mechanisms by which high fat, high cholesterol, and high fructose (HFCF) diet promotes liver steatosis, inflammation and fibrosis remains poorly understood. The overall objective of this proposal aims to investigate the role of b-ZIP transcription repressor E4 promoter- binding protein 4 (E4BP4) in driving diet-induced NAFLD in mice. Our preliminary data demonstrated loss of hepatic E4BP4 protects mice against high-fat diet-induced liver steatosis and E4BP4 promotes the expression of Cidea and Fsp27-β, two major lipid droplet binding proteins, in the liver in response to high-fat diet. We also discovered that chronic high-fat diet feeding leads to deSUMOylation of E4BP4 in the liver. Moreover, hepatocytes expressing a non-SUMOylatable E4BP4 show more lipid droplet formation than those of WT- E4BP4. Thus, we hypothesize that E4BP4 deSUMOylation promotes liver steatosis and its progression by increasing lipid biosynthesis and storage during diet-induced fatty liver disease. We will test the central hypothesis by pursuing the following three specific aims: 1. Determine the pathologic role of E4BP4 in promoting HFCF diet-induced NAFLD using liver-specific E4bp4 knockout mice. 2. Uncover molecular pathways of how hepatic E4BP4 promotes lipid accumulation via elevating Cidea and Fsp27-β expression in hepatocytes and the liver during diet-induced NAFLD. 3. Investigate the function and regulation of deSUMOylation of hepatic E4BP4 in the pathogenesis of diet- induced NAFLD. Our study will uncover hepatocyte-specific E4BP4 as a crucial regulator that connects HFCF diet and NAFLD. The completion of the proposed study will gain critical knowledge regarding the molecular pathways driven by E4BP4 to promote the onset and progression of NAFLD. The novel knowledge will shed light on novel preventive or therapeutic measures to treat NAFDL by targeting E4BP4 expression or SUMOylation.

非酒精肝疾病（NAFLD）是最常见的肝病，到目前为止，NAFDL的NAFDS已有NAFLD患者的NAFLD患者，从简单的脂肪变性到非酒精性脂肪性脂肪炎（NASH），并最终生活失败对于肝脏衰竭的NAFLD的患者，富含脂肪，胆固醇和果糖和NAFLD的饮食中，该提案的分子机制旨在研究B-ZIP转录抑制剂E4促进蛋白4 （E4BP4）在驱动小鼠饮食引起的NAFLD时，我们的初步数据表明，肝E4BP4的损失可保护小鼠小鼠小鼠P4促进CIDEA和FSP27-β的表达脂肪饮食。饮食中的肝脏SE。肝脏诱导的肝E4BP4的NAFLD在饮食诱发的NAFLD的发病机理中治疗表达或sumoylation。