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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Dokumenter

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

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.

OriginalsprogEngelsk
TidsskriftCell Reports
Vol/bind19
Udgave nummer9
Sider (fra-til)1794-1806
Antal sider13
ISSN2211-1247
DOI
StatusUdgivet - 30 maj 2017

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