Mechanisms of ER stress - induced fatty liver

内质网应激诱发脂肪肝的机制

• 批准号: 8288740
• 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/8288740
• 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

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。项目摘要/摘要 脂肪肝病（FLD）有多种原因，包括长期饮酒，肥胖，病毒感染， FLD可以从简单的脂肪变类到脂肪性肝炎 这会损害肝功能，导致炎症，纤维化，肝硬化和最终导致肝衰竭。尽管 FLD最有可能反映出脂质合成，储存，氧化和/或分泌之间的不平衡 这种不平衡的基本分子原因只能部分理解。作为酒鬼和 非酒精性起源非常普遍，识别其病因可能会有所不同，这将表明途径 治疗以防止肝衰竭。该研究建议基于强大的初步数据证明 内质网应力（ER）应力导致对维持涉及的基因的转录抑制 脂质稳态；在ER应力敏感蛋白ATF6上，遗传缺陷的小鼠无法克服ER 压力，并在挑战中变得深深地呈肉毒杆菌。这些动物，否则在 未受伤的状态，提供了一种有价值的工具，用于剖析ER应力与肝脏脂质之间的连接 代谢。这项工作的长期目的是了解ER扰动如何促进 脂肪肝病。这一目标将通过三个完整的投资领域实现。第一个目的是 要了解如何在机械上与脂质体内稳态的机械响应在 转录。基因调节事件将根据体内的能力放置为层次结构 关键代谢转录因子的过表达，以部分或完全挽救ATF6 null小鼠的脂肪变性。在 通过ER应力调节的转录因子对基因的平行，直接调节将通过两种无偏见进行探测 并靶向染色质免疫沉淀。最后，与代谢转录联系的机制 将确定对未解决的ER应力的调节。第二个目的是确定如何调节 ER应力反应反过来影响ER功能。这个目标将通过 指出脂质代谢的途径，这些脂质代谢在ER应力期间有助于脂肪变性，并测试如何 当这些途径为 操纵独立于ER应力。第三个目的是确定慢性ER应力如何促进 病理脂肪变性，特别是酒精脂肪肝病。我们将使用atf6¿ -NOTULL小鼠测试是否 ER功能的损害会在慢性乙醇消耗期间感知小鼠对脂肪变性。我们也会 确定慢性乙醇消耗如何通过ER应力调节的变化来改变细胞稳态 在基因表达中。这项工作提供了几种独立的途径来解决发展的一个方面 目前知之甚少的脂肪变性，并将确定可能的新型关键调节途径 代表了未来治疗干预以防止肝衰竭的有吸引力的目标。