ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

Diane DeZwaan-McCabe; Ryan D Sheldon; Michelle C Gorecki; Deng-Fu Guo; Erica R Gansemer; Randal J Kaufman; Kamal Rahmouni; Matthew P Gillum; Eric B Taylor; Lynn M Teesch; D. Thomas Rutkowski

doi:10.1016/j.celrep.2017.05.020

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ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

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ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

Diane DeZwaan-McCabe, Ryan D Sheldon, Michelle C Gorecki, Deng-Fu Guo, Erica R Gansemer, Randal J Kaufman, Kamal Rahmouni, Matthew P Gillum, Eric B Taylor, Lynn M Teesch, …

Cell reports (Cambridge), Vol.19(9), pp.1794-1806

05/30/2017

DOI: 10.1016/j.celrep.2017.05.020

PMCID: PMC5520660

PMID: 28564599

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Abstract

The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. [Display omitted] •ER stress directly targets the liver and kidneys, and both organs accumulate lipid•Inhibition of fatty acid oxidation contributes to hepatic steatosis•Animals that cannot mitigate ER stress become anorexic•Lipolysis exacerbates steatosis in the liver and kidney of sensitive animals The mechanisms by which the liver and kidney become steatotic when challenged by ER stress are not known. DeZwaan-McCabe et al. show that ER stress inhibits fatty acid oxidation in the liver and that unmitigated stress causes anorexia and promotes adipose lipolysis and further steatosis in the liver and kidney.

unfolded protein response

fatty kidney

ER stress

fatty liver

fatty acid oxidation

lipolysis

lipidomics

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Title: Subtitle: ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis
Creators: Diane DeZwaan-McCabe - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Ryan D Sheldon - Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Michelle C Gorecki - Section for Metabolic Imaging and Liver Metabolism, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark
Deng-Fu Guo - Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Erica R Gansemer - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Randal J Kaufman - Degenerative Diseases Program, SBP Medical Discovery Institute, La Jolla, CA 92037, USA
Kamal Rahmouni - Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Matthew P Gillum - Section for Metabolic Imaging and Liver Metabolism, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark
Eric B Taylor - Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lynn M Teesch - High Resolution Mass Spectrometry Facility, University of Iowa, Iowa City, IA 52242, USA
D. Thomas Rutkowski - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.19(9), pp.1794-1806
Publisher: Elsevier Inc
DOI: 10.1016/j.celrep.2017.05.020
PMID: 28564599
PMCID: PMC5520660
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: name: NIH, award: GM115424; name: University of Iowa Department of Anatomy and Cell Biology; DOI: 10.13039/100015515, name: Carver College of Medicine; name: Office of the Vice President for Research (OVPR); DOI: 10.13039/100000968, name: American Heart Association (AHA), award: 14POST20420015; name: NIH, award: HL07734; name: NIH, award: DK104998; DOI: 10.13039/100008893, name: University of Iowa; name: OVPR; name: NIH, award: HL084207; name: AHA, award: 14EIA18860041; name: University of Iowa Fraternal Order of Eagles Diabetes Research Center; name: NIH, award: DK042394, DK103185, DK110973, CA198103; DOI: 10.13039/501100011747, name: Novo Nordisk Foundation Center for Basic Metabolic Research
Language: English
Date published: 05/30/2017
Academic Unit: Neurology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Core Research Facilities; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Medicine Administration; Internal Medicine
Record Identifier: 9984025356602771

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