High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis
Open Access
- 30 March 2020
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 34 (5), 6888-6906
- https://doi.org/10.1096/fj.201903119r
Abstract
Previously, we identified a mechanism of inflammation control directed by ribosomal protein L13a and “GAIT” (Gamma Activated Inhibitor of Translation) elements in target mRNAs and showed that its elimination in myeloid cell-specific L13a knockout mice (L13a KO) increased atherosclerosis susceptibility and severity. Here, we investigated the mechanistic basis of this endogenous defense against atherosclerosis. We compared molecular and cellular aspects of atherosclerosis in high-fat diet (HFD)-fed L13a KO and intact (control) mice. HFD treatment of control mice induced release of L13a from 60S ribosome, formation of RNA-binding complex, and subsequent GAIT element-mediated translational silencing. Atherosclerotic plaques from HFD-treated KO mice showed increased infiltration of M1 type inflammatory macrophages. Macrophages from KO mice showed increased phagocytic activity and elevated expression of LDL receptor and pro-inflammatory mediators. NanoString analysis of the plaques from KO mice showed upregulation of a number of mRNAs encoding inflammatory proteins. Bioinformatics analysis suggests the presence of the potential GAIT elements in the 3′UTRs of several of these mRNAs. Macrophage induces L13a/GAIT-dependent translational silencing of inflammatory genes in response to HFD as an endogenous defense against atherosclerosis in ApoE−/− model.Keywords
Funding Information
- National Heart, Lung, and Blood Institute (HL79164)
- National Institute of Allergy and Infectious Diseases (AI087586)
- Cleveland State University, Center for Gene Regulation in Health and Disease
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