Genomic and Metabolomic Responses to Alcohol-induced Liver Damage

描述（由申请人提供）： 酒精消费占全球疾病负担的4%，在美国是第三大与生活方式相关的死亡原因，部分原因是酒精性肝病（ALD）引起的并发症。除肥胖外，长期饮酒导致肝脏游离脂肪酸（FFA）水平过高，抑制氧化途径，最终导致肝脏疾病（脂肪变性、炎症、肝肿大、纤维化和肝硬化）。有趣的是，在人类和小鼠模型中，酒精对肝脏的不良影响似乎部分是由于过氧化物酶体增殖物激活受体α（PPARa）的衰减。酒精喂养的PPara-无效小鼠作为在人类中观察到的ALD的极好模型，并强调了PPARa在保护免受ALD中的重要性。此外，该小鼠模型已在超过750篇出版物中引用，支持其在理解PPARa作用方面的重要实用性。PPARa的影响机制将被确定为ALD的潜在治疗干预策略和用于早期检测这种疾病的生物标志物的开发。为此，设计了以下具体目标：1）将酒精诱导的肝损伤与在酒精喂养的Ppara缺失小鼠中鉴定的基因表达和代谢组学生物标志物相关联，以开发特异性ALD生物标志物。2)确定与饮酒后小鼠模型中PPARa表达降低相关的潜在表观遗传和转录后变化;和3）使用原代肝细胞培养物开发酒精诱导损伤类型的毒理基因组学和毒理代谢组学特征。这些目标旨在了解和整合与ALD相关的组织病理学，基因组学和代谢组学改变，以开发与ALD发病机制相关的早期生物标志物。长期饮酒可导致酒精性肝损伤（ALD），这是由于氧化途径受损和随后的脂肪肝发展。过氧化物酶体增殖物激活受体α（PPARa）是氧化的关键调节因子。缺乏PPARa的酒精喂养小鼠会产生类似人类的ALD，在本项目中，将用于开发指示ALD进展的生物标志物。

DESCRIPTION (provided by applicant): Alcohol consumption contributes to 4% of the global disease burden and in the United States is the third leading lifestyle-related cause of death due in part to complications arising from alcohol-induced liver disease (ALD). In addition to obesity, chronic alcohol consumption leads to excessive hepatic free fatty acid (FFA) levels that inhibit ¿-oxidation pathways and ultimately cause liver disease (steatosis, inflammation, hepatomegaly, fibrosis, and cirrhosis). Interestingly, the adverse effects of alcohol on the liver, in humans and in mouse models, appear to be due, in part, to attenuation of the peroxisome-proliferator activated receptor alpha (PPARa). The alcohol-fed Ppara-null mouse serves as an excellent model for ALD observed in humans and underscores the importance of PPARa in protecting against ALD. Additionally, this mouse model has been cited in over 750 publications supporting its significant utility in understanding the role of PPARa. The mechanism of the influence of PPARa will be determined for potential therapeutic intervention strategies on ALD and for the development of biomarkers for early detection of this disease. To this end, the following specific aims were designed: 1) To correlate alcohol-induced liver damage with gene expression and metabolomic biomarkers identified in alcohol-fed Ppara-null mice for the purpose of developing specific ALD biomarkers.; 2) To identify potential epigenetic and post-transcriptional changes associated with decreased PPARa expression in mouse models following alcohol consumption; and 3) To develop toxicogenomic and toxicometabolomic signatures for types of alcohol-induced injury using primary hepatocyte cultures. These aims seek to understand and integrate the histopathological, genomic, and metabolomic alterations associated with ALD for the purpose of developing early biomarkers associated with ALD pathogenesis. Chronic alcohol consumption can lead to alcohol-induced liver damage (ALD) due to the impairment of ¿-oxidation pathways and subsequent development of fatty liver. A key regulator of ¿-oxidation is the peroxisome-proliferator activated receptor alpha (PPARa). Alcohol-fed mice lacking PPARa develop human-like ALD and in this project will be used to develop biomarkers that are indicative of ALD progression.