title: Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish.
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.
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Ana M
authors: AM
authors: Vacaru
authors: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Antonio Fabio
authors: AF
authors: Di Narzo
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Deanna L
authors: DL
authors: Howarth
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Orkhontuya
authors: O
authors: Tsedensodnom
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Dru
authors: D
authors: Imrie
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Ayca
authors: A
authors: Cinaroglu
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA.
authors: Salma
authors: S
authors: Amin
authors: Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ke
authors: K
authors: Hao
authors: Department of Medicine/Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, Box 1020, 1 Gustave L. Levy Place, New York, NY 10029, USA. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Kirsten.edepli@mssm.edu.
authors: Kirsten C
authors: KC
authors: Sadler
mesh_terms: D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D006031:Glycosylation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; D014415:Tunicamycin; D020126:Brefeldin A; D019284:Thapsigargin
keywords: ER stress; Fatty liver disease; Steatosis; Thapsigargin; Tunicamycin; Unfolded protein response; Zebrafish