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%，在美国是与生活方式有关的第三大死亡原因，部分原因是酒精引起的肝病(ALD)引起的并发症。除了肥胖之外，长期饮酒还会导致肝脏游离脂肪酸(FFA)水平过高，从而抑制氧化途径，最终导致肝脏疾病(脂肪变性、炎症、肝肿大、纤维化和肝硬变)。有趣的是，在人类和小鼠模型中，酒精对肝脏的不利影响似乎部分是由于过氧化体-增殖物激活受体α(PPARa)的减弱。酒精喂养的Ppara缺失小鼠是在人类中观察到的ALD的极好模型，并强调了PPARa在预防ALD中的重要性。此外，这个小鼠模型已经被750多种出版物引用，支持它在理解PPARa作用方面的重要作用。PPARa影响ALD的机制将被确定为ALD的潜在治疗干预策略和早期发现这种疾病的生物标记物的开发。为此，设计了以下特定目标：1)将酒精诱导的肝损伤与酒精喂养的Ppara缺失小鼠中确定的基因表达和代谢组生物标记物相关联，以开发特定的ALD生物标记物。2)确定与酒精消费后小鼠模型中PPARa表达降低相关的潜在的表观遗传和转录后变化；以及3)利用原代肝细胞培养，为不同类型的酒精诱导损伤建立毒理基因组学和毒物代谢组学特征。这些目标旨在了解和整合与ALD相关的组织病理学、基因组和代谢改变，以开发与ALD发病相关的早期生物标记物。长期饮酒可导致氧化途径受损，继而发展为脂肪肝，从而导致酒精性肝损伤(ALD)。氧化的一个关键调节因子是过氧化物酶体增殖物激活受体α(PPARa)。缺乏PPARa的酒精喂养的小鼠会出现类似人类的ALD，在这个项目中，将被用来开发指示ALD进展的生物标记物。

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.