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Mechanisms of ER stress - induced fatty liver

内质网应激诱发脂肪肝的机制

基本信息

批准号：
8586223
负责人：
David Thomas Rutkowski
金额：
$ 0.15万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586223
关键词：
Acute Address Adult Affect Alcoholic Fatty Liver Alcohols American Animals Area Biochemical CCAAT-Enhancer-Binding Proteins Cell physiology Chronic Cirrhosis Client Country Data Development Endoplasmic Reticulum Etiology Event Exposure to Family member Fatty Liver Fibrosis Functional disorder Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Hepatic Homeostasis Human Impairment Inflammation Investigation Knockout Mice Lead Link Lipids Liver Liver Failure Liver diseases Malnutrition Mediating Metabolic Metabolic Pathway Metabolic syndrome Metabolism Molecular Mus Obesity Organ Organelles Pathway interactions Physiological Play Process Proteins Proteome Regulation Regulator Genes Regulatory Pathway Research Proposals Site Steatohepatitis Stress Stress Tests System Testing Therapeutic Intervention Toxin Transcriptional Regulation Up-Regulation Very low density lipoprotein Virus Diseases Work abstracting base biological adaptation to stress chromatin immunoprecipitation chronic alcohol ingestion clinically relevant design effective therapy endoplasmic reticulum stress fatty acid oxidation hepatotoxin human disease improved in vivo lipid metabolism liver function non-alcoholic novel overexpression oxidation prevent problem drinker protein folding protein misfolding public health relevance research study response secretory protein tool transcription factor transcription factor ATF6

项目摘要

Item 6. Project Summary/Abstract Fatty liver disease (FLD) has a variety of causes including chronic alcohol consumption, obesity, viral infection, malnutrition, and acute exposure to hepatotoxins. FLD can progress from simple steatosis to steatohepatitis that compromises liver function, leading to inflammation, fibrosis, cirrhosis, and ultimately liver failure. While FLD most likely reflects an imbalance between lipid synthesis, storage, oxidation, and/or secretion, the underlying molecular causes of this imbalance are only partially understood. As FLD of both alcoholic and nonalcoholic origins is very common, identifying its etiologies, which are likely varied, will suggest avenues of treatment to prevent liver failure. This research proposal is based upon strong preliminary data demonstrating that endoplasmic reticulum (ER) stress leads to transcriptional suppression of genes involved in maintaining lipid homeostasis; mice genetically deficient in the ER stress-sensing protein ATF6¿ fail to overcome ER stress, and become profoundly steatotic upon challenge. These animals, which are otherwise normal in the uninjured state, provide a valuable tool for dissecting the connections between ER stress and liver lipid metabolism. The long-term objective of this work is to understand how ER perturbation contributes to fatty liver disease. This goal will be achieved by three complementary areas of investigation. The first aim is to understand how the ER stress response is mechanistically connected to lipid homeostasis at the level of transcription. Gene regulatory events will be placed into a hierarchy based on the ability of in vivo overexpression of key metabolic transcription factors to partially or fully rescue steatosis in Atf6¿-null mice. In parallel, direct regulation of genes by ER stress-regulated transcription factors will be probed by both unbiased and targeted chromatin immunoprecipitation. Finally, the mechanism that ties metabolic transcriptional regulation to unresolved ER stress will be determined. The second aim is to determine how the regulation of lipid metabolism by the ER stress response in turn impacts ER function. This aim will be achieved by pinpointing the pathways of lipid metabolism that contribute to steatosis during ER stress, and testing how the ability of the ER to fold and process client proteins (i.e., "ER function") is altered when these pathways are manipulated independent of ER stress. The third aim is to determine how chronic ER stress contributes to pathological steatosis, in particular alcoholic fatty liver disease. We will use Atf6¿-null mice to test whether impairment of ER function sensitizes mice to steatosis during chronic ethanol consumption. We will also determine how chronic ethanol consumption alters cellular homeostasis through ER stress-regulated changes in gene expression. This work provides several independent avenues to address an aspect of the development of steatosis that is currently poorly understood, and will identify novel key regulatory pathways that might represent attractive targets for future therapeutic intervention to prevent liver failure.

项目6。项目总结/文摘