biostudies-literatureTufanli OTürkiye Bilimsel ve Teknolojik Arastirma KurumuEuropean Research CouncilHoward Hughes Medical InstituteE1395-E1404https://www.ebi.ac.uk/biostudies/studies/S-EPMC5338400biostudies-literatureUnknown114(8)Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenProceedings of the National Academy of Sciences of the United States of AmericaTargeting IRE1 with small molecules counteracts progression of atherosclerosis.PMC5338400336643110S293113Z023InvestigatorTelkoparan Akillilar PAcosta-Alvear DCimen IKocaturk BWeber CErbay EHamid SMTufanli OOnat UIWalter PfalseTargeting IRE1 with small molecules counteracts progression of atherosclerosis.Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogen2017-01-01T00:00:00Z2017 Feb2025-04-26T18:02:02.594Z2019-03-27T02:37:53ZS-EPMC53384002813785610.1073/pnas.1621188114