Journal article
Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress
Molecular biology of the cell, Vol.23(5), pp.811-819
03/2012
DOI: 10.1091/mbc.e11-12-1011
PMCID: PMC3290641
PMID: 22262455
Abstract
The unfolded protein response (UPR) signals protein misfolding in the endoplasmic reticulum (ER) to effect gene expression changes and restore ER homeostasis. Although many UPR-regulated genes encode ER protein processing factors, others, such as those encoding lipid catabolism enzymes, seem unrelated to ER function. It is not known whether UPR-mediated inhibition of fatty acid oxidation influences ER function or, if so, by what mechanism. Here we demonstrate that pharmacological or genetic inhibition of fatty acid oxidation renders liver cells partially resistant to ER stress–induced UPR activation both in vitro and in vivo. Reduced stress sensitivity appeared to be a consequence of increased cellular redox potential as judged by an elevated ratio of oxidized to reduced glutathione and enhanced oxidative folding in the ER. Accordingly, the ER folding benefit of inhibiting fatty acid (FA) oxidation could be phenocopied by manipulating glutathione recycling during ER stress. Conversely, preventing cellular hyperoxidation with N-acetyl cysteine partially negated the stress resistance provided by blocking FA oxidation. Our results suggest that ER stress can be ameliorated through alteration of the oxidizing environment within the ER lumen, and they provide a potential logic for the transient regulation of metabolic pathways by the UPR during stress.
Details
- Title: Subtitle
- Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress
- Creators
- Heather M Tyra - Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA 52242D. Thomas Rutkowski - Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242
- Contributors
- Ramanujan S Hegde (Editor)
- Resource Type
- Journal article
- Publication Details
- Molecular biology of the cell, Vol.23(5), pp.811-819
- DOI
- 10.1091/mbc.e11-12-1011
- PMID
- 22262455
- PMCID
- PMC3290641
- NLM abbreviation
- Mol Biol Cell
- ISSN
- 1059-1524
- eISSN
- 1939-4586
- Publisher
- American Society for Cell Biology
- Language
- English
- Date published
- 03/2012
- Academic Unit
- Anatomy and Cell Biology; Pathology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984046820902771
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