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：
8096833
负责人：
David Thomas Rutkowski
金额：
$ 25.73万
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/8096833
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 Health 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 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

DESCRIPTION (provided by applicant): 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 ATF61 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 Atf61-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 Atf61-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. PUBLIC HEALTH RELEVANCE: Public Health Relevance Steatosis, or fatty liver disease, is the most common liver disease in Western countries, being present in approximately 25 percent of American adults; it can progress to steatohepatitis, fibrosis, cirrhosis, and liver failure. The causes underlying the development of steatosis are not clear, and must be understood for effective therapies to be developed. The identification of endoplasmic reticulum stress as a contributing factor to steatosis suggests that the work proposed here will enhance our understanding of molecular basis for steatosis and suggest means of therapeutically treating it.

描述（由申请人提供）：脂肪肝病（FLD）有多种原因，包括长期饮酒、肥胖、病毒感染、营养不良和急性接触肝毒素。 FLD 可从单纯性脂肪变性进展为损害肝功能的脂肪性肝炎，导致炎症、纤维化、肝硬化，最终导致肝衰竭。虽然 FLD 很可能反映了脂质合成、储存、氧化和/或分泌之间的不平衡，但这种不平衡的潜在分子原因尚不清楚。由于酒精性和非酒精性 FLD 都很常见，因此确定其病因（可能多种多样）将为预防肝衰竭的治疗途径提供建议。该研究提案基于强有力的初步数据，表明内质网（ER）应激会导致参与维持脂质稳态的基因转录抑制；内质网应激感应蛋白 ATF61 基因缺陷的小鼠无法克服内质网应激，并在受到挑战后变得严重脂肪变性。这些动物在未受伤的状态下是正常的，为剖析内质网应激和肝脏脂质代谢之间的联系提供了有价值的工具。这项工作的长期目标是了解内质网扰动如何导致脂肪肝疾病。这一目标将通过三个互补的研究领域来实现。第一个目标是了解内质网应激反应如何在转录水平上与脂质稳态相关。基因调控事件将根据关键代谢转录因子体内过表达部分或完全拯救 Atf61 缺失小鼠脂肪变性的能力进行分级。同时，将通过无偏和靶向染色质免疫沉淀来探测内质网应激调节转录因子对基因的直接调节。最后，将确定代谢转录调控与未解决的内质网应激之间的联系机制。第二个目的是确定内质网应激反应对脂质代谢的调节反过来如何影响内质网功能。这一目标将通过查明内质网应激期间导致脂肪变性的脂质代谢途径，并测试当这些途径独立操作时，内质网折叠和加工客户蛋白的能力（即“内质网功能”）如何改变来实现。 ER 压力。第三个目标是确定慢性内质网应激如何导致病理性脂肪变性，特别是酒精性脂肪肝。我们将使用 Atf61 缺失小鼠来测试 ER 功能受损是否会使小鼠在长期乙醇消耗期间对脂肪变性敏感。我们还将确定长期乙醇消耗如何通过内质网应激调节的基因表达变化来改变细胞稳态。这项工作提供了几种独立的途径来解决目前人们知之甚少的脂肪变性发展的一个方面，并将确定新的关键调控途径，这些途径可能代表未来预防肝衰竭治疗干预的有吸引力的目标。公共健康相关性：公共健康相关性脂肪变性或脂肪肝疾病是西方国家最常见的肝脏疾病，大约 25% 的美国成年人患有这种疾病；它可以进展为脂肪性肝炎、纤维化、肝硬化和肝功能衰竭。脂肪变性发生的原因尚不清楚，必须了解其原因才能开发有效的治疗方法。内质网应激被认为是脂肪变性的一个促成因素，这表明本文提出的工作将增强我们对脂肪变性分子基础的理解，并提出治疗方法。