Chronic or repetitive binge alcohol consumption is known to lead to alcoholic liver disease (ALD) which encompasses several different phenotypes (e.g., cirrhosis, fatty liver disease, hepatitis, and susceptibility to liver cancer). Additionally alcoholics are routinely immuno-compromised and therefore at heightened risk for additional challenges from opportunistic pathogens. While these examples of tissue damage are well studied, explanations of the underlying cellular mechanisms remain less clear. Furthermore, the relevance of these rapid and transient cellular consequences have not been significantly addressed in binge models of alcohol consumption. The goal of this work is to investigate the effect of ethanol on the sphingolipid metabolic pathway, and study the phenotypes that occur as a result of this interaction. Using genetically modified cell culture or in vivo mouse models of ethanol exposure, we aim to address the mechanisms that alter within the cell. We will focus on two particular contexts to study the outcome of ethanol-mediated modulation of the sphingolipid pathway. (1) We will utilize cell culture models of ALD and primary murine hepatocytes to study disruptions to apoptotic machinery as a consequence of ethanol-mediated inhibition of sphingolipid metabolism. We will also validate our findings using histology of human samples from a biorepository. (2) We will characterize the nature by which sphingolipid metabolism inhibition due to ethanol effects lymphocyte egress from lymph nodes and the thymus. Isolations of tissues, serum, and lymph in these mice will conducted to assess levels of critical enzymes, lipids, and mature lymphocytes. Completion of these aims will aid in the underlying cellular mechanisms that result in the chronic phenotypes associated with ALD. Additionally, this new perspective on ethanol response will result in new opportunities for therapeutics to alleviate some of these diseases in patients suffering from addiction to alcohol.
This application seeks to understand how ethanol expsosure disrupts the sphingolipid metabolic pathway, and results in particular phenotypes associated with alcoholic liver disease. Understanding of this underlying mechanism and fundamental biology will provide novel therapeutic targets to alleviate diseases and challenges of patients addicted to alcohol.
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