Alcoholic Liver Disease (ALD) remains a major cause of alcohol-related morbidity and mortality. 15-30% of heavy drinkers develop advanced ALD, over 25,000 deaths occur annually related to liver disease, and over 40% of those are attributed to alcoholic cirrhosis. Major advances have been made in our understanding of mechanisms of ALD, especially related to oxidative stress, cytokines, mitochondrial dysfunction and adduct formation. However, there is no FDA-approved therapy for alcoholic hepatitis or cirrhosis, and our understanding concerning disease pathogenesis remains incomplete. The emergence of the obesity epidemic (non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as the hepatic manifestations of the metabolic syndrome) has provided new insights into mechanisms of liver injury. The """"""""two-hit"""""""" theory for NASH that a baseline of fatty liver plus one of multiple second """"""""hits"""""""" initiates the progression from steatosis to more serious liver injury, steatohepatitis. Similarly, most patients who drink heavily develop steatosis but only a few develop steatohepatitis, and similar mechanisms or """"""""hits"""""""" for disease progression to alcoholic steatohepatitis (ASH) have been postulated. Lastly, we have recently reported that environmental toxicants (TASH) can produce steatohepatitis indistinguishable histologically from that produced by obesity or alcohol. We are in a unique situation to utilize a proteomics/ metabolomics approach for discovery of biomarkers for alcoholic liver disease and specifically alcoholic steatohepatitis. We have a one-of-a-kind database/repository in which we have a large number of serum/plasma specimens from well-characterized patients with severe alcoholic hepatitis, well-characterized NASH, and a highly-novel patient population of well-characterized TASH. Thus, we will be able to compare/ contrast the proteomics/metabolomics signatures in specimens from well-characterized patients with diverse steatohepatitis. We will also compare the results from the human ASH studies with experimental ASH samples from our ULARC rodent repository.
Specific Aims of this proposal address the following 3 questions: 1) Are there biomarkers determined by proteomics/metabolomics that are common to ASH, NASH and TASH that indicate mechanistic commonalities in steatohepatitis?;2) Are there unique biomarkers for ASH compared with NASH/TASH?;and 3) Are there biomarkers for ASH that predict prognosis/outcomes?

Public Health Relevance

The Research Area explored in this proposal is """"""""Molecular Markers of Alcohol Exposure and Alcohol-Induced Tissue Injury"""""""". We postulate that there are metabolic pathways and biomarkers that can be defined by proteomics and metabolomics that are common to Alcoholic Steatohepatitis (ASH), Non-Alcoholic Steatohepatitis (NASH) and Toxicant Associated Steatohepatitis (TASH). Furthermore, we predict that ASH may have unique biomarkers/metabolic pathways, and differences may be seen in patients who resolve their disease compared to those who are having ongoing injury or die.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
High Impact Research and Research Infrastructure Programs (RC2)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG (02))
Program Officer
Radaeva, Svetlana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Song, Ming; Chen, Theresa; Prough, Russell A et al. (2016) Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response. Alcohol Clin Exp Res 40:518-28
Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang et al. (2015) Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats. Am J Physiol Gastrointest Liver Physiol 308:G934-45
Liu, Yanlong; Ma, Zhenhua; Zhao, Cuiqing et al. (2014) HIF-1? and HIF-2? are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1?-mediated fatty acid ?-oxidation. Toxicol Lett 226:117-23
Shi, Xue; Wei, Xiaoli; Koo, Imhoi et al. (2014) Metabolomic analysis of the effects of chronic arsenic exposure in a mouse model of diet-induced Fatty liver disease. J Proteome Res 13:547-554
Ghare, Smita S; Joshi-Barve, Swati; Moghe, Akshata et al. (2014) Coordinated histone H3 methylation and acetylation regulate physiologic and pathologic fas ligand gene expression in human CD4+ T cells. J Immunol 193:412-21
Wei, Xiaoli; Shi, Xue; Kim, Seongho et al. (2014) Data dependent peak model based spectrum deconvolution for analysis of high resolution LC-MS data. Anal Chem 86:2156-65
Watson, Walter H; Burke, Tom J; Doll, Mark A et al. (2014) S-adenosylhomocysteine inhibits NF-?B-mediated gene expression in hepatocytes and confers sensitivity to TNF cytotoxicity. Alcohol Clin Exp Res 38:889-96
Smart, Laura; Gobejishvili, Leila; Crittenden, Neil et al. (2013) Alcoholic Hepatitis: Steroids vs. Pentoxifylline. Curr Hepat Rep 12:59-65
Wang, Yuhua; Liu, Yanlong; Kirpich, Irina et al. (2013) Lactobacillus rhamnosus GG reduces hepatic TNF? production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem 24:1609-15
Wahlang, Banrida; Beier, Juliane I; Clair, Heather B et al. (2013) Toxicant-associated steatohepatitis. Toxicol Pathol 41:343-60

Showing the most recent 10 out of 45 publications