DeZwaan-McCabe Diane, Sheldon Ryan D, Gorecki Michelle C, Guo Deng-Fu, Gansemer Erica R, Kaufman Randal J, Rahmouni Kamal, Gillum Matthew P, Taylor Eric B, Teesch Lynn M, Rutkowski D Thomas
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Cell Rep. 2017 May 30;19(9):1794-1806. doi: 10.1016/j.celrep.2017.05.020.
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.
内质网（ER）应激诱导的未折叠蛋白反应（UPR）可调节恢复蛋白质折叠稳态的因子的表达。然而，在肝脏和肾脏中，ER应激也会导致脂质积累，至少在肝脏中伴随着代谢基因的转录抑制。这种积累的机制，包括哪些途径导致每个器官中的表型，尚不清楚。我们结合基因表达谱分析、生化分析和非靶向脂质组学，利用缺乏ER应激传感器ATF6α的小鼠中肝脏和肾脏脂肪变性增强的情况，来了解应激依赖性脂质积累的基础。我们发现，脂肪酸氧化受损促成了肝脏而非肾脏脂肪变性的早期发展，而厌食诱导的脂肪分解促进了两个器官中甘油三酯和游离脂肪酸的后期积累。这些发现为ER应激对外周代谢的直接和间接调节提供了证据。
