Both genetic and environmental factors modulate the effects of alcohol on the liver. For instance, theconsequences of alcohol abuse vary between ethnic groups, and patients with steatosis are sensitized toalcohol induced liver damage. Both alcohol and lipid accumulation induce oxidative stress in hepatocytes,and it is hypothesized that through the induction of oxidative stress and the resultant endoplasmic reticulum(ER) stress, alcohol potentiates damage in fatty livers. However, the genes that participate in this processare not well defined. Zebrafish are a widely used vertebrate model, and the availability of mutants andmorpholinos to knock-down target genes in embryos is an excellent system for determining the geneticcontribution to developmental and physiologic processes. Previous work suggests that ethanol treatment ofearly stage zebrafish embryos results in phenotypes similar to those of the fetal alcohol syndrome.Antioxidant treatment partially abrogates these teratogenic effects, suggesting that, as in mammals,oxidative stress is a central mechanism by which alcohol causes cellular damage in zebrafish embryos. Thezebrafish liver is mature by days 4-5 of development, and our preliminary results show that treating theselate stage embryos with 1-2% ethanol causes hepatomegaly and steatosis. Additionally, cyp2e1, markers ofoxidative and endoplasmic reticulum (ER) stress, and genes involved in cholesterol biogenesis areupregulated by ethanol in a dose-dependent manner. Thus zebrafish provide a novel model system toinvestigate the genetic basis for liver damage induced by alcohol, and will allow inquiry into the role ofoxidative stress. Furthermore, homozygous mutation of the novel gene foie gras (fgr) results in molecularand histological features of fatty liver disease on day 5 of development, including signs of decreased hepaticfunction, liver injury, and ER stress in hepatocytes, followed by embryonic death on day 7. Our datademonstrate that fgr embryos are sensitized to alcohol toxicity and fgr+/- adults, while viable and fertile, aresensitized to hepatic injury. We will use this model to investigate the genetic basis for alcohol-induceddamage of steatotic livers.
Specific aims are: 1. To develop an alcohol induced liver injury model in zebrafishembryos. 2. Identify genetic modifiers of alcohol induced liver damage in zebrafish. 3. To investigate theinteraction between steatosis, oxidative stress, and liver damage in the fgr model of fatty liver disease.
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