C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Madhusudana R Chikka; Diane DeZwaan McCabe; Heather M Tyra; D. Thomas Rutkowski

doi:10.1074/jbc.M112.432344

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C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Journal article

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C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Madhusudana R Chikka, Diane DeZwaan McCabe, Heather M Tyra and D. Thomas Rutkowski

The Journal of biological chemistry, Vol.288(6), pp.4405-4415

02/2013

DOI: 10.1074/jbc.M112.432344

PMCID: PMC3567690

PMID: 23281479

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Abstract

The unfolded protein response (UPR) senses stress in the endoplasmic reticulum (ER) and initiates signal transduction cascades that culminate in changes to gene regulation. Long recognized as a means for improving ER protein folding through up-regulation of ER chaperones, the UPR is increasingly recognized to play a role in the regulation of metabolic pathways. ER stress is clearly connected to altered metabolism in tissues such as the liver, but the mechanisms underlying this connection are only beginning to be elucidated. Here, working exclusively in vivo, we tested the hypothesis that the UPR-regulated CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) participates in the transcriptional regulation of metabolism during hepatic ER stress. We found that metabolic dysregulation was associated with induction of eIF2α signaling and CHOP up-regulation during challenge with tunicamycin or Velcade. CHOP was necessary for suppression of genes encoding the transcriptional master regulators of lipid metabolism: Cebpa, Ppara, and Srebf1. This action of CHOP required a contemporaneous CHOP-independent stress signal. CHOP bound directly to C/EBP-binding regions in the promoters of target genes, whereas binding of C/EBPα and C/EBPβ to the same regions was diminished during ER stress. Our results thus highlight a role for CHOP in the transcriptional regulation of metabolism. Background: ER stress regulates metabolic gene expression in liver. Results: The ER stress-regulated pro-apoptotic transcription factor CHOP binds to the promoters of metabolic genes and is necessary for their suppression. Conclusion: CHOP contributes to the metabolic alterations that accompany ER stress in vivo. Significance: These findings suggest that CHOP has a non-apoptotic role in regulating metabolic physiology.

Gene Transcription

Unfolded protein Response

CHOP

Metabolism

Endoplasmic Reticulum Stress

Endoplasmic Reticulum (ER)

Details

Title: Subtitle: C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver
Creators: Madhusudana R Chikka - From the Departments of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
Diane DeZwaan McCabe - From the Departments of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
Heather M Tyra - From the Departments of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
D. Thomas Rutkowski - From the Departments of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.288(6), pp.4405-4415
DOI: 10.1074/jbc.M112.432344
PMID: 23281479
PMCID: PMC3567690
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Language: English
Date published: 02/2013
Academic Unit: Microbiology and Immunology; Anatomy and Cell Biology; Internal Medicine
Record Identifier: 9984094319102771

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