Mechanisms of ER stress - induced fatty liver

内质网应激诱发脂肪肝的机制

• 批准号: 7848143
• 负责人: David Thomas Rutkowski
• 金额: $ 37.13万
• 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/7848143
• 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; Role; 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

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(申请人提供)：脂肪肝(FLD)有多种原因，包括长期饮酒、肥胖、病毒感染、营养不良和急性暴露于肝毒素。FLD可从单纯的脂肪变性发展为脂肪性肝炎，损害肝功能，导致炎症、纤维化、硬化，最终导致肝功能衰竭。虽然FLD很可能反映了脂肪合成、储存、氧化和/或分泌之间的失衡，但这种失衡的潜在分子原因只被部分了解。由于酒精性和非酒精性FLD非常常见，确定其病因可能是不同的，这将为预防肝功能衰竭提供治疗途径。这项研究建议基于强大的初步数据，证明内质网(ER)应激导致维持脂质稳态相关基因的转录抑制；ER应激敏感蛋白ATF61的遗传缺陷小鼠无法克服ER应激，并在受到挑战时变得严重脂肪变性。这些动物在未损伤状态下是正常的，为解剖内质网应激和肝脂代谢之间的联系提供了一个有价值的工具。这项工作的长期目标是了解内质网扰动是如何导致脂肪肝的。这一目标将通过三个相辅相成的调查领域来实现。第一个目的是了解内质网应激反应是如何在转录水平上机械地与脂质稳态联系在一起的。基因调控事件将根据体内关键代谢转录因子的过度表达来部分或完全修复Atf61基因缺失小鼠的脂肪变性的能力而被归类。同时，内质网应激调节转录因子对基因的直接调控将通过无偏染色质免疫沉淀和靶向染色质免疫沉淀来探索。最后，将确定代谢转录调控与未解决的内质网应激有关的机制。第二个目的是确定内质网应激反应对脂代谢的调节如何反过来影响内质网功能。这一目标将通过以下方式实现：查明在内质网应激过程中导致脂肪变性的脂肪代谢途径，并测试当这些途径独立于内质网应激而被操纵时，内质网折叠和处理客户蛋白的能力(即“内质网功能”)是如何改变的。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基因缺失的小鼠来测试内质网功能受损是否会使小鼠在慢性酒精消费过程中对脂肪变性敏感。我们还将确定慢性酒精消费如何通过内质网应激调节基因表达的变化来改变细胞动态平衡。这项工作提供了几个独立的途径来解决脂肪变性发展的一个方面，目前对此知之甚少，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功能衰竭的治疗干预的有吸引力的靶点。与公共健康相关：脂肪变性，或称脂肪肝，是西方国家最常见的肝病，约25%的美国成年人患有此病；它可发展为脂肪性肝炎、纤维化、肝硬变和肝功能衰竭。脂肪变性发生的潜在原因尚不清楚，必须了解才能开发出有效的治疗方法。内质网应激是导致脂肪变性的一个因素，这表明本文提出的工作将加强我们对脂肪变性的分子基础的理解，并提出治疗方法。