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

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): 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.

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Teaser

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.


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