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

Deanna L. Howarth, Mike Passeri, Kirsten Sadler Edepli

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)826-829
Number of pages4
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number5
DOIs
StatePublished - May 1 2011

Fingerprint

Alcoholic Liver Diseases
Zebrafish
Liver
Fish
Fishes
Alcohols
Larva
Binge Drinking
Genes
Fertilization
Vertebrates
Transcription Factors
Lipogenesis
Hepatomegaly
Response Elements
Sterols
Gene encoding
Oxidative stress
Alcoholism
Ports and harbors

Keywords

  • Alcohol
  • Steatosis
  • Zebrafish

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Drinks Like a Fish : Using Zebrafish to Understand Alcoholic Liver Disease. / Howarth, Deanna L.; Passeri, Mike; Sadler Edepli, Kirsten.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 5, 01.05.2011, p. 826-829.

Research output: Contribution to journalArticle

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