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

TY - JOUR

T1 - ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

AU - DeZwaan-McCabe, Diane

AU - Sheldon, Ryan D

AU - Gorecki, Michelle C

AU - Guo, Deng-Fu

AU - Gansemer, Erica R

AU - Kaufman, Randal J

AU - Rahmouni, Kamal

AU - Gillum, Matthew P

AU - Taylor, Eric B

AU - Teesch, Lynn M

AU - Rutkowski, D Thomas

N1 - Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2017/5/30

Y1 - 2017/5/30

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.celrep.2017.05.020

DO - 10.1016/j.celrep.2017.05.020

M3 - Journal article

C2 - 28564599

SN - 2639-1856

VL - 19

SP - 1794

EP - 1806

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -