Journal article
UPR Pathways Combine to Prevent Hepatic Steatosis Caused by ER Stress-Mediated Suppression of Transcriptional Master Regulators
Developmental cell, Vol.15(6), pp.829-840
2008
DOI: 10.1016/j.devcel.2008.10.015
PMCID: PMC2923556
PMID: 19081072
Abstract
The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how endoplasmic reticulum (ER) disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress-sensing pathways (ATF6α, eIF2α, IRE1α) or of ER quality control (p58
IPK) share a common dysregulated response to ER stress that includes the development of hepatic microvesicular steatosis. Rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism, and suggest mechanisms by which ER stress might underlie fatty liver disease.
Details
- Title: Subtitle
- UPR Pathways Combine to Prevent Hepatic Steatosis Caused by ER Stress-Mediated Suppression of Transcriptional Master Regulators
- Creators
- D. Thomas Rutkowski - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJun Wu - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USASung-Hoon Back - Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USAMichael U Callaghan - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USASean P Ferris - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJahangir Iqbal - Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USARobert Clark - Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USAHongzhi Miao - Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJustin R Hassler - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJamie Fornek - Department of Microbiology, University of Washington, Seattle, WA 98195, USAMichael G Katze - Department of Microbiology, University of Washington, Seattle, WA 98195, USAM. Mahmood Hussain - Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USABenbo Song - Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJayanth Swathirajan - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USAJunying Wang - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USAGrace D.-Y Yau - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USARandal J Kaufman - Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
- Resource Type
- Journal article
- Publication Details
- Developmental cell, Vol.15(6), pp.829-840
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.devcel.2008.10.015
- PMID
- 19081072
- PMCID
- PMC2923556
- ISSN
- 1534-5807
- eISSN
- 1878-1551
- Language
- English
- Date published
- 2008
- Academic Unit
- Anatomy and Cell Biology; Internal Medicine
- Record Identifier
- 9984094390102771
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