Alcohol consumption can have life-threatening effects on human health; in fact, the overall disease burden from alcohol is estimated to exceed 3% of deaths throughout the world. The consequences of alcohol are particularly severe in the liver where alcohol is metabolized and leads to Alcoholic Liver Disease (ALD). ALD occurs as a variety of conditions including fatty liver (steatosis), hepatitis, fibrosis, and hepatocellular carcinoma (HCC). Other behaviors with adverse effects on health, such as smoking, often coincide with alcohol consumption, patients under-report their consumption of alcohol, and there is substantial genetic variation across the population; therefore, elucidating the mechanisms underlying ALD in patients presents a number of significant challenges. To overcome these challenges in ALD research, we developed a Drosophila (fruit fly) model of ALD using the Drosophila organ most similar to the mammalian liver, a bipartite organ of the ?fat body? and the ?oenocytes.? Strikingly, the fat body significantly increases in size (organomegaly) in larvae exposed to alcohol, reminiscent of mammalian ethanol-induced hepatomegaly. Existing animal models for ALD have some advantages but also face certain limitations. Drosophila recapitulate many phenomena relevant to disease, and this model system has been used effectively to model diverse conditions from autism to cancer. Drosophila represent an ideal system to explore effects of genetic susceptibility, including germline or somatic mutations in specific tissues, combined with environmental exposure such as exposure to alcohol and other forms of oxidative stress. Although our Drosophila ALD model also faces limitations, it bypasses some inherent limitations of existing animal models and brings the power of Drosophila genetics to the study of ALD, namely (1) 10-day generation time, (2) the ease of performing a large number of parallel genetic interaction studies, (3) the utility of descriptive phenotypic analysis, (4) the ability to address the functional relevance of candidate molecules in physiological setting, and (5) the wealth of genetic tools and reagents. Thus, our Drosophila ALD model provides an extremely practical, rapid, efficient, and cost- effective system for discovery and for developing meaningful mechanistic hypotheses to then address in vertebrate models. Establishing the Drosophila fat body and oenocytes as a model to study ALD will be a tremendous resource and make a significant impact on the field. Flies are also an excellent in vivo system capable of simultaneously evaluating chemical compound stability, bioavailability, toxicity, and efficacy in modifying disease-relevance phenotypes. In summary, our Drosophila ALD model is a valuable resource that complements existing ALD model systems to significantly advance our understanding of the etiology of ALD and to serve as a platform for drug discovery.
Alcoholic Liver Disease (ALD) comprises a range of conditions including fatty liver disease, fibrosis, and hepatocellular carcinoma and causes significant mortality on a global scale. Therefore, it is a crucial to understand the etiology of ALD. The proposed studies will have a significant impact on ALD research by (1) establishing a Drosophila model of ALD amenable to genetic mechanistic analysis and adaptable as a platform for drug discovery for this devastating disease, and (2) by identifying genetic and chemical modifiers in this model system.
