Dataset Information
Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis.
Ontology highlight
ABSTRACT: Background
Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2?) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2? phosphorylation is observed in mouse and human atheroma.Objectives
Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis.Methods
The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes.Results
The results show lipid-activated eIF2? signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1? secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis.Conclusions
These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2?-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1? secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.
SUBMITTER: Onat UI
PROVIDER: S-EPMC6424590 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis.
Journal of the American College of Cardiology 20190301 10
<h4>Background</h4>Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.<h4>Objectives</h4>Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated t ...[more]
