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

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

doi:10.1242/dmm.014472

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.

Highlights

The authors report that principal component analysis of unfolded protein response (UPR) target gene induction serves as a marker of the stressed UPR in zebrafish livers and that this same principal component applied to samples from patients with fatty liver disease reveals UPR induction in these individuals
This study provides a novel perspective on the well-established link between UPR activation and Fatty liver disease (FLD)
Many studies have found some aspects of the UPR induced in FLD samples, and this has led to an oversimplification of the relationship between UPR activation and FLD, whereby any indicator of UPR activation is equated with endoplasmic reticulum (ER) stress and that all stressors that generate UPR induction cause FLD

Summary

Introduction

The unfolded protein response (UPR) allows cells to adapt to changing physiological demands and to extreme stress by enhancing protein folding and quality control in the endoplasmic reticulum (ER) and by modulating the influx of nascent proteins into the ER The responses to different stressors are nuanced and dynamic, eliciting different combinations of UPR sensor and target gene activation that fluctuate with the nature and duration of the stressor These different UPRs have different outcomes, which can alternatively prevent or promote disease. UPR activation provides a first-line defense against secretory pathway stress by reducing the unfolded protein burden in the ER and restoring homeostasis In this case, UPR activation is beneficial, as it allows cells to withstand and adapt to stress (Rutkowski and Kaufman, 2007). Little is known about how different stressors translate to clinically relevant outcomes (Walter and Ron, 2011)

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