Mechanisms of ER stress - induced fatty liver

内质网应激诱发脂肪肝的机制

• 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
• 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

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（FLD）有多种原因，包括慢性饮酒、肥胖、病毒感染、营养不良和急性暴露于肝毒素。FLD可以从简单的脂肪变性发展为损害肝功能的脂肪性肝炎，导致炎症、纤维化、肝硬化，最终导致肝功能衰竭。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仅部分了解。由于酒精性和非酒精性来源的FLD非常常见，因此确定其病因（可能不同）将提示预防肝衰竭的治疗途径。这项研究建议是基于强有力的初步数据表明，内质网（ER）应激导致参与维持脂质稳态的基因的转录抑制; ER应激传感蛋白ATF 61基因缺陷的小鼠无法克服ER应激，并在挑战后变得严重脂肪变性。这些动物在未受伤状态下是正常的，为解剖ER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ER扰动如何导致脂肪肝疾病。这一目标将通过三个相辅相成的调查领域来实现。第一个目的是了解ER应激反应是如何在转录水平上与脂质稳态机械连接的。基因调控事件将根据关键代谢转录因子的体内过表达部分或完全挽救Atf 61缺失小鼠脂肪变性的能力被置于层级中。同时，ER应激调节转录因子对基因的直接调节将通过无偏和靶向染色质免疫沉淀来探测。最后，将代谢转录调节与未解决的ER应激联系起来的机制将被确定。第二个目的是确定ER应激反应对脂质代谢的调节如何反过来影响ER功能。这一目标将通过精确定位在ER应激期间促成脂肪变性的脂质代谢途径，并测试ER如何折叠和加工客户蛋白（即，当这些途径不依赖于ER应激而被操纵时，这些途径（即“ER功能”）被改变。第三个目的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Atf 61-null小鼠来测试ER功能的损伤是否使小鼠在慢性乙醇消耗期间对脂肪变性敏感。我们还将确定慢性乙醇消耗如何通过内质网应激调节基因表达的变化来改变细胞内稳态。这项工作提供了几个独立的途径来解决目前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治疗干预的有吸引力的靶点，以预防肝衰竭。公共卫生关系：脂肪变性或脂肪肝是西方国家最常见的肝病，约占美国成年人的25%;它可以进展为脂肪性肝炎，纤维化，肝硬化和肝功能衰竭。脂肪变性发展的潜在原因尚不清楚，必须了解有效的治疗方法。内质网应激作为脂肪变性的一个促成因素的鉴定表明，这里提出的工作将提高我们对脂肪变性的分子基础的理解，并提出治疗方法。