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

Ana M. Vacaru, Antonio Fabio Di Narzo, Deanna L. Howarth, Orkhontuya Tsedensodnom, Dru Imrie, Ayca Cinaroglu, Salma Amin, Ke Hao, Kirsten Sadler Edepli

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)823-835
    Number of pages13
    JournalDMM Disease Models and Mechanisms
    Volume7
    Issue number7
    DOIs
    StatePublished - Jan 1 2014

    Fingerprint

    Unfolded Protein Response
    Zebrafish
    Fatty Liver
    Liver
    Liver Diseases
    Proteins
    Chemical activation
    Genes
    Tunicamycin
    Thapsigargin
    Sensors
    Principal Component Analysis
    Endoplasmic Reticulum
    Principal component analysis
    Brefeldin A
    Protein Folding

    Keywords

    • ER stress
    • Fatty liver disease
    • Steatosis
    • Thapsigargin
    • Tunicamycin
    • Unfolded protein response
    • Zebrafish

    ASJC Scopus subject areas

    • Neuroscience (miscellaneous)
    • Medicine (miscellaneous)
    • Immunology and Microbiology (miscellaneous)
    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Vacaru, A. M., Di Narzo, A. F., Howarth, D. L., Tsedensodnom, O., Imrie, D., Cinaroglu, A., ... Sadler Edepli, K. (2014). Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish. DMM Disease Models and Mechanisms, 7(7), 823-835. https://doi.org/10.1242/dmm.014472

    Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish. / Vacaru, Ana M.; Di Narzo, Antonio Fabio; Howarth, Deanna L.; Tsedensodnom, Orkhontuya; Imrie, Dru; Cinaroglu, Ayca; Amin, Salma; Hao, Ke; Sadler Edepli, Kirsten.

    In: DMM Disease Models and Mechanisms, Vol. 7, No. 7, 01.01.2014, p. 823-835.

    Research output: Contribution to journalArticle

    Vacaru, AM, Di Narzo, AF, Howarth, DL, Tsedensodnom, O, Imrie, D, Cinaroglu, A, Amin, S, Hao, K & Sadler Edepli, K 2014, 'Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish', DMM Disease Models and Mechanisms, vol. 7, no. 7, pp. 823-835. https://doi.org/10.1242/dmm.014472
    Vacaru, Ana M. ; Di Narzo, Antonio Fabio ; Howarth, Deanna L. ; Tsedensodnom, Orkhontuya ; Imrie, Dru ; Cinaroglu, Ayca ; Amin, Salma ; Hao, Ke ; Sadler Edepli, Kirsten. / Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish. In: DMM Disease Models and Mechanisms. 2014 ; Vol. 7, No. 7. pp. 823-835.
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    AU - Imrie, Dru

    AU - Cinaroglu, Ayca

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