PUBLICATION

Drinks Like a Fish: Using Zebrafish to Understand Alcoholic Liver Disease

Authors
Howarth, D.L., Passeri, M., and Sadler, K.C.
ID
ZDB-PUB-110207-22
Date
2011
Source
Alcoholism, clinical and experimental research   35(5): 826-829 (Journal)
Registered Authors
Howarth, Deanna, Sadler Edepli, Kirsten C.
Keywords
Zebrafish, Alcohol, Steatosis
MeSH Terms
  • Alcohol Drinking/genetics
  • Alcohol Drinking/metabolism*
  • Alcohol Drinking/pathology
  • Animals
  • Comprehension*
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Ethanol/administration & dosage
  • Fatty Liver/genetics
  • Fatty Liver/metabolism
  • Fatty Liver/pathology
  • Humans
  • Liver Diseases, Alcoholic/genetics
  • Liver Diseases, Alcoholic/metabolism*
  • Liver Diseases, Alcoholic/pathology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
PubMed
21284674 Full text @ Alcoholism Clin. Exp. Res.
Abstract
Steatosis is the most common consequence of acute alcohol abuse, such as occurs during a drinking binge. Acute alcohol induced steatosis may predispose to more severe hepatic disease. We have developed a model of alcoholic liver disease (ALD) in zebrafish larvae to provide a system in which the genes and pathways that contribute to steatosis can be rapidly identified. Zebrafish larvae represent an attractive vertebrate model for studying acute ALD because they possess the pathways to metabolize alcohol, the liver is mature by 4 days post-fertilization (dpf), and alcohol can be simply added to their water. Exposing 4 dpf zebrafish larvae to 2% ethanol (EtOH) for 32 hours achieves ∼80 mM intracellular EtOH and upregulation of hepatic cyp2e1, sod, and bip, indicating that EtOH is metabolized and provokes oxidative stress. EtOH-treated larvae develop ALD as demonstrated by hepatomegaly and steatosis. Increased lipogenesis driven by the sterol response element binding protein (SREBP) transcription factors is essential for steatosis associated with chronic alcohol ingestion but it has not been determined if the same pathway is essential for steatosis following a drinking binge. We report that several Srebp target genes are induced in the liver of zebrafish exposed to EtOH. We used fish which harbor a mutation in the gene encoding the membrane bound transcription factor protease 1 (mbtps1; also called site-1 protease) and embryos in which the Srebp cleavage activating protein (scap) is knocked down to determine the requirement of this pathway in acute ALD. We find that both means of blocking Srebp activation prevents steatosis in response to 2% EtOH. Moreover, this is accompanied by the failure to activate several Srebp target genes in response to alcohol. We conclude that Srebps are required for steatosis in response to acute alcohol exposure. Moreover, these data highlight the utility of zebrafish as a useful new vertebrate model to study ALD.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping