Author + information
- Received June 6, 2018
- Revision received December 7, 2018
- Accepted December 10, 2018
- Published online March 11, 2019.
- Umut I. Onat, BSca,b,
- Asli D. Yildirim, MSca,b,c,d,
- Özlem Tufanli, PhDa,b,
- Ismail Çimen, PhDa,b,
- Begüm Kocatürk, PhDa,b,e,
- Zehra Veli, MSca,b,
- Syed M. Hamid, PhDc,d,
- Kenichi Shimada, PhDc,f,g,
- Shuang Chen, MD, PhDc,g,h,
- Jon Sin, PhDc,d,
- Prediman K. Shah, MDd,f,
- Roberta A. Gottlieb, MD, PhDc,d,
- Moshe Arditi, MDc,d,g,h and
- Ebru Erbay, MD, PhDa,b,c,d,∗ (, )@CedarsSinai
- aDepartment of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
- bNational Nanotechnology Center, Bilkent University, Ankara, Turkey
- cDepartment of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
- dSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California
- eDepartment of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, California
- fDivision of Cardiology, Oppenheimer Atherosclerosis Research Center and Atherosclerosis Prevention and Treatment Center, Cedars-Sinai Medical Center, Los Angeles, California
- gDepartments of Medicine and Pediatrics, Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, California
- hDavid Geffen School of Medicine, University of California, Los Angeles, California
- ↵∗Address for correspondence:
Dr. Ebru Erbay, Department of Medicine, Smidt Heart Institute & Department of Biomedical Sciences, Cedars Sinai Medical Center, 127 South San Vincente Boulevard, Advanced Health Sciences Pavilion, A9104, Los Angeles, California 90048.
Background 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.
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 eIF2α 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-1β 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 eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β 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.
- dietary fats
- integrated stress response
- lipid-induced inflammation
- metabolic inflammation
Dr. Tufanli’s current address is NYU Langone Medical Center, New York University, New York, New York. Dr. Çimen’s current address is the Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany. This work was funded by the EMBO installation grant and ERC Starting Grant (336643) (to Dr. Erbay). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received June 6, 2018.
- Revision received December 7, 2018.
- Accepted December 10, 2018.
- 2019 The Authors