PUBLICATION

Atf6 plays protective and pathologic roles in fatty liver disease due to endoplasmic reticulum stress

Authors
Cinaroglu, A., Gao, C., Imrie, D., and Sadler, K.C.
ID
ZDB-PUB-110519-27
Date
2011
Source
Hepatology (Baltimore, Md.)   54(2): 495-508 (Journal)
Registered Authors
Cinaroglu, Ayca, Gao, Chuan, Imrie, Dru, Sadler Edepli, Kirsten C.
Keywords
foie gras, unfolded protein response, steatosis, zebrafish, tunicamycin
MeSH Terms
  • Activating Transcription Factor 6/physiology*
  • Animals
  • Endoplasmic Reticulum*
  • Fatty Liver/etiology*
  • Fatty Liver/genetics
  • Mutation
  • Stress, Physiological*
  • Zebrafish
  • Zebrafish Proteins/genetics
(all 9)
PubMed
21538441 Full text @ Hepatology
Abstract
Many etiologies of fatty liver disease (FLD) are associated with hyper-activation of one of the three pathways that comprise the unfolded protein response (UPR), a harbinger of endoplasmic reticulum (ER) stress. The UPR is mediated by pathways initiated by PERK, IRE1a/XBP1and ATF6, and each of these pathways have been implicated as either protective or pathological in FLD. We use zebrafish with FLD and hepatic ER stress to explore the relationship between Atf6 and steatosis. Mutation of the foie gras (foigr) gene causes FLD and hepatic ER stress. Prolonged treatment of wild-type larvae with a dose of tunicamycin that causes chronic ER stress phenocopies foigr. In contrast, acute exposure to a high dose of tunicamycin robustly activates the UPR but is less effective at inducing steatosis. The Srebp transcription factors are not required for steatosis in any of these models. Instead, depleting larvae of active Atf6 either through mbtps1 mutation or atf6 morpholino injection protects against steatosis caused by chronic ER stress whereas it exacerbates steatosis caused by acute tunicamycin treatment. Conclusion: ER stress causes FLD. Loss of Atf6 prevents steatosis caused by chronic ER stress but can also potentiate steatosis caused by acute ER stress. This demonstrates that Atf6 can play both protective and pathological roles in FLD.
Genes / Markers
Figures
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO2-scapfastingDay 6
gz15Tg + MO1-atf6standard conditionsDay 5
gz15Tg + MO1-atf6standard conditionsDay 5
mbtps1hi1487Tgstandard conditionsDay 5
mbtps1hi1487Tgstandard conditionsDay 5
trappc11hi1532bTgcontrolDay 5
trappc11hi1532bTgstandard conditionsDay 5
trappc11hi1532bTgstandard conditionsDay 5
trappc11hi1532bTgstandard conditionsDay 5
trappc11hi1532bTgstandard conditionsDay 5
1 - 10 of 22
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gz15TgTransgenic Insertion
    hi1487TgTransgenic Insertion
    hi1532bTgTransgenic Insertion
    1 - 3 of 3
    Show
    Human Disease / Model
    Sequence Targeting Reagents
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    DsRedEFGDsRed
    EGFPEFGEGFP
    1 - 2 of 2
    Show
    Mapping
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    Citation
    Cinaroglu, A., Gao, C., Imrie, D., and Sadler, K.C. (2011) Atf6 plays protective and pathologic roles in fatty liver disease due to endoplasmic reticulum stress. Hepatology (Baltimore, Md.). 54(2):495-508.