Intercepting the lipid-induced integrated stress response reduces atherosclerosis

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buir.contributor.authorOnat, Umut I.
buir.contributor.authorYıldırım, Aslı D.
buir.contributor.authorTufanlı, Özlem
buir.contributor.authorÇimen, İsmail
buir.contributor.authorKocatürk, Begüm
buir.contributor.authorVeli, Zehra
buir.contributor.authorErbay, Ebru
dc.citation.epage1169en_US
dc.citation.issueNumber10en_US
dc.citation.spage1149en_US
dc.citation.volumeNumber73en_US
dc.contributor.authorOnat, Umut I.en_US
dc.contributor.authorYıldırım, Aslı D.en_US
dc.contributor.authorTufanlı, Özlemen_US
dc.contributor.authorÇimen, İsmailen_US
dc.contributor.authorKocatürk, Begümen_US
dc.contributor.authorVeli, Zehraen_US
dc.contributor.authorHamid, S.en_US
dc.contributor.authorShimada, K.en_US
dc.contributor.authorChen, S.en_US
dc.contributor.authorSin, J.en_US
dc.contributor.authorShah, P.en_US
dc.contributor.authorGottlieb, R.en_US
dc.contributor.authorArditi, M.en_US
dc.contributor.authorErbay, Ebruen_US
dc.date.accessioned2020-02-12T11:12:55Z
dc.date.available2020-02-12T11:12:55Z
dc.date.issued2019
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentNanotechnology Research Center (NANOTAM)en_US
dc.description.abstractBackground 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.en_US
dc.identifier.doi10.1016/j.jacc.2018.12.055en_US
dc.identifier.issn0735-1097
dc.identifier.urihttp://hdl.handle.net/11693/53304
dc.language.isoEnglishen_US
dc.publisherElsevieren_US
dc.relation.isversionofhttps://doi.org/10.1016/j.jacc.2018.12.055en_US
dc.source.titleJournal of the American College of Cardiologyen_US
dc.subjectAtherosclerosisen_US
dc.subjectDietary fatsen_US
dc.subjectInflammasomeen_US
dc.subjectIntegrated stress responseen_US
dc.subjectInterleukin-1βen_US
dc.subjectLipid-induced inflammationen_US
dc.subjectMationmetabolic inflammationen_US
dc.titleIntercepting the lipid-induced integrated stress response reduces atherosclerosisen_US
dc.typeArticleen_US

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Department of Molecular Biology and Genetics
Nanotechnology Research Center (NANOTAM)