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. 项目总结/摘要 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脂肪性肝炎 损害肝功能，导致炎症、纤维化、肝硬化，最终导致肝衰竭。尽管 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， 这种不平衡的根本分子原因仅被部分了解。作为酒精和酒精的 FLD 非酒精起源很常见，确定其病因（可能多种多样）将提出解决问题的途径 治疗以预防肝衰竭。该研究提案基于强有力的初步数据证明 内质网（ER）应激导致参与维持的基因转录抑制 脂质稳态；遗传缺陷内质网应激感应蛋白 ATF6 的小鼠无法克服内质网 压力，并在受到挑战时变得严重脂肪变性。这些动物在其他方面是正常的 未受伤状态，为剖析内质网应激和肝脂质之间的联系提供了一个有价值的工具 代谢。这项工作的长期目标是了解 ER 扰动如何影响 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机制上与脂质稳态相关 转录。基因调控事件将根据体内能力进行分级 关键代谢转录因子的过度表达可部分或完全挽救 Atf6¿ 缺失小鼠的脂肪变性。在 内质网应激调节转录因子对基因的平行、直接调节将通过无偏见的探索 和靶向染色质免疫沉淀。最后，将代谢转录联系起来的机制 将确定对未解决的 ER 应激的调节。第二个目标是确定如何监管 内质网应激反应引起的脂质代谢反过来又影响内质网功能。这一目标将通过以下方式实现 查明 ER 应激期间导致脂肪变性的脂质代谢途径，并测试 当这些途径被改变时，内质网折叠和加工客户蛋白的能力（即“内质网功能”）就会改变。 独立于 ER 压力进行操作。第三个目标是确定慢性 ER 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 Atf6¿-null 小鼠来测试是否 内质网功能受损使小鼠在长期乙醇消耗过程中对脂肪变性敏感。我们还将 确定长期乙醇消耗如何通过内质网应激调节的变化改变细胞稳态 在基因表达方面。这项工作提供了几种独立的途径来解决开发的一个方面 目前对脂肪变性知之甚少，并将确定可能的新的关键调控途径 代表了未来预防肝衰竭治疗干预的有吸引力的目标。