Both genetic and environmental factors modulate the effects of alcohol on the liver. For instance, the consequences of alcohol abuse vary between ethnic groups, and patients with steatosis are sensitized to alcohol 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 process are not well defined. Zebrafish are a widely used vertebrate model, and the availability of mutants and morpholinos to knock-down target genes in embryos is an excellent system for determining the genetic contribution to developmental and physiologic processes. Previous work suggests that ethanol treatment of early 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. The zebrafish liver is mature by days 4-5 of development, and our preliminary results show that treating these late stage embryos with 1-2% ethanol causes hepatomegaly and steatosis. Additionally, cyp2e1, markers of oxidative and endoplasmic reticulum (ER) stress, and genes involved in cholesterol biogenesis are upregulated by ethanol in a dose-dependent manner. Thus zebrafish provide a novel model system to investigate the genetic basis for liver damage induced by alcohol, and will allow inquiry into the role of oxidative stress. Furthermore, homozygous mutation of the novel gene foie gras (fgr) results in molecular and histological features of fatty liver disease on day 5 of development, including signs of decreased hepatic function, liver injury, and ER stress in hepatocytes, followed by embryonic death on day 7. Our data demonstrate that fgr embryos are sensitized to alcohol toxicity and fgr+/- adults, while viable and fertile, are sensitized to hepatic injury. We will use this model to investigate the genetic basis for alcohol-induced damage of steatotic livers.
Specific aims are: 1. To develop an alcohol induced liver injury model in zebrafish embryos. 2. Identify genetic modifiers of alcohol induced liver damage in zebrafish. 3. To investigate the interaction between steatosis, oxidative stress, and liver damage in the fgr model of fatty liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017067-05
Application #
8380256
Study Section
Special Emphasis Panel (ZAA1-BB)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$82,232
Indirect Cost
$33,719
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Renault, Thibaud T; Floros, Konstantinos V; Elkholi, Rana et al. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69-82
Kocabayoglu, Peri; Lade, Abigale; Lee, Youngmin A et al. (2015) β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol 63:141-7
Kocabayoglu, Peri; Zhang, David Y; Kojima, Kensuke et al. (2015) Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice. Liver Int :
Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro et al. (2015) Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. Mol Cell Biol 35:1543-56
Lade, Abigale; Noon, Luke A; Friedman, Scott L (2014) Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr Opin Oncol 26:100-7
Renault, Thibaud T; Elkholi, Rana; Bharti, Archana et al. (2014) B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. J Biol Chem 289:26481-91
Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie et al. (2014) In vivo cell biology in zebrafish - providing insights into vertebrate development and disease. J Cell Sci 127:485-95
Arriazu, Elena; Ruiz de Galarreta, Marina; Cubero, Francisco Javier et al. (2014) Extracellular matrix and liver disease. Antioxid Redox Signal 21:1078-97
Ge, Xiaodong; Antoine, Daniel J; Lu, Yongke et al. (2014) High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J Biol Chem 289:22672-91
Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335

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