Journal
CELL REPORTS
Volume 19, Issue 9, Pages 1794-1806Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.020
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Funding
- NIH [GM115424, HL07734, DK104998, HL084207, DK042394, DK103185, DK110973, CA198103]
- University of Iowa Department of Anatomy and Cell Biology
- Carver College of Medicine
- Office of the Vice President for Research (OVPR)
- American Heart Association (AHA) [14POST20420015]
- University of Iowa Healthcare Research Investment Pilot Grant
- OVPR
- AHA [14EIA18860041]
- University of Iowa Fraternal Order of Eagles Diabetes Research Center
- Novo Nordisk Foundation Center
- University of Copenhagen
- Novo Nordisk Foundation
- NNF Center for Basic Metabolic Research [Gillum Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0009525, NNF15SA0018486] Funding Source: researchfish
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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 ATF6 alpha. 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.
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