MSACL 

17. In Search of Non-Invasive Biomarkers for Alcohol-Induced Liver Damage
**MOVED TO TUESDAY 12:18 Track 1**
Mon 12:18 PM - PosterSplash Track 1
Soumen K. Manna
NCI
Soumen K. Manna, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;
Andrew D. Patterson, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;
Qian Yang, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057;
Kristopher W. Krausz, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;
Henghong Li, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057;
Jeffrey R. Idle, Institute of Clinical Pharmacology and Visceral Research, University of Bern, 3010 Bern, Switzerland;
Albert J. Fornace, Jr., Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057;
Frank J. Gonzalez, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland;
Alcohol consumption contributes to 4% of the global disease burden and in the United States it is the third leading lifestyle-related cause of death due in part to complications arising from alcohol-induced liver damage (ALD). Unfortunately, an early and reliable diagnostic biomarker for ALD is lacking. In addition to obesity, chronic alcohol consumption leads to excessive hepatic free fatty acid levels that inhibit beta-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 (PPARalpha). The nuclear transcriptional factor PPARalpha serves a fundamental role in mammals by acting as a central modulator of signaling molecules that mediate changes in gene expression to maintain lipid homeostasis. The alcohol-fed Ppara-null mouse serves as an excellent model for ALD observed in humans as it has been found to develop ALD with marked similarity to the initial stages of human ALD pathogenesis. Metabolomics, which aims at quantitative profiling of all small molecules (‘metabolome’) in bio-fluids, therefore, offers an exciting opportunity to explore biomarkers for ALD in this animal model. The inherent sensitivity of the metabolic machinery to endogeneous and exogeneous perturbations predisposes it as a valuable gauge to monitor pathophysiology. The UPLC-ESI-TOFMS platform was used for global metabolic profiling of urine samples collected from control (maltose dextran used to balance the ethanol calories) and ethanol-fed (4% in liquid diet) wild-type and Ppara-null mice over a period of 6 months. Multivariate data analysis could easily distinguish the ethanol-treated mice from the control animals in both supervised and unsupervised models. It also helped to select ions that contributed to the separation of these groups on ethanol exposure. More than 75 ions were found to be significantly modulated {-0.8 > p(corr) > 0.8} with ethanol feeding. Finally, the identity of some of these ions were established and their urinary concentrations were measured. Metabolites related to aromatic amino acid metabolism, which is regulated by PPARalpha, were elevated exclusively in the ethanol-treated Ppara-null mice that recollect the early stages of human ALD. These findings may not only help to validate non-invasive urinary biomarkers for ethanol exposure and ALD but also guide future research to elucidate the molecular level phenomena associated with the onset of ALD.
Email: [email protected]