Genomic and Metabolomic Responses to Alcohol-induced Liver Damage

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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.