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
Affiliations
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
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.
