PUBLICATION

Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish

Authors
Vacaru, A.M., Di Narzo, A.F., Howarth, D.L., Tsedensodnom, O., Imrie, D., Cinaroglu, A., Amin, S., Hao, K., Sadler, K.C.
ID
ZDB-PUB-140629-5
Date
2014
Source
Disease models & mechanisms   7: 823-835 (Journal)
Registered Authors
Cinaroglu, Ayca, Howarth, Deanna, Imrie, Dru, Sadler Edepli, Kirsten C., Vacaru, Ana
Keywords
ER stress, Fatty liver disease, Steatosis, Thapsigargin, Tunicamycin, Unfolded protein response, Zebrafish
MeSH Terms
  • Animals
  • Brefeldin A/pharmacology
  • DNA-Binding Proteins/metabolism
  • Endoplasmic Reticulum Stress/drug effects
  • Endoplasmic Reticulum Stress/genetics
  • Fatty Liver/genetics*
  • Fatty Liver/pathology*
  • Fatty Liver/prevention & control
  • Glycosylation/drug effects
  • Heat-Shock Proteins/metabolism
  • Liver/drug effects
  • Liver/pathology
  • Thapsigargin/pharmacology
  • Transcription Factors/metabolism
  • Tunicamycin
  • Unfolded Protein Response/drug effects
  • Unfolded Protein Response/genetics*
  • Up-Regulation/drug effects
  • Up-Regulation/genetics
  • Zebrafish/genetics*
  • Zebrafish Proteins/metabolism
PubMed
24973751 Full text @ Dis. Model. Mech.
Abstract
The unfolded protein response (UPR) is a complex network of sensors and target genes that ensure efficient folding of secretory proteins in the endoplasmic reticulum (ER). UPR activation is mediated by three main sensors, which regulate the expression of hundreds of targets. UPR activation can result in outcomes ranging from enhanced cellular function to cell dysfunction and cell death. How this pathway causes such different outcomes is unknown. Fatty liver disease (steatosis) is associated with markers of UPR activation and robust UPR induction can cause steatosis; however, in other cases, UPR activation can protect against this disease. By assessing the magnitude of activation of UPR sensors and target genes in the liver of zebrafish larvae exposed to three commonly used ER stressors (tunicamycin, thapsigargin and Brefeldin A), we have identified distinct combinations of UPR sensors and targets (i.e. subclasses) activated by each stressor. We found that only the UPR subclass characterized by maximal induction of UPR target genes, which we term a stressed-UPR, induced steatosis. Principal component analysis demonstrated a significant positive association between UPR target gene induction and steatosis. The same principal component analysis showed significant correlation with steatosis in samples from patients with fatty liver disease. We demonstrate that an adaptive UPR induced by a short exposure to thapsigargin prior to challenging with tunicamycin reduced both the induction of a stressed UPR and steatosis incidence. We conclude that a stressed UPR causes steatosis and an adaptive UPR prevents it, demonstrating that this pathway plays dichotomous roles in fatty liver disease.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping