ZFIN ID: ZDB-PUB-110519-27
Atf6 plays protective and pathologic roles in fatty liver disease due to endoplasmic reticulum stress
Cinaroglu, A., Gao, C., Imrie, D., and Sadler, K.C.
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
PubMed: 21538441 Full text @ Hepatology
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.