Palmitic Acid-Induced Long Noncoding RNA Regulates Inflammation via Interaction With RNA-Binding Protein ELAVL1 in Monocytes and Macrophages.

Background: Obesity and diabetes are associated with elevated free fatty acids like palmitic acid (PA), which promote chronic inflammation and impaired inflammation resolution associated with cardiometabolic disorders. Long noncoding RNAs (lncRNAs) are implicated in inflammatory processes; however, their roles in PA-regulated inflammation and resolution are unclear.

Methods: We performed RNA-sequencing analysis to identify PA-regulated coding genes and novel lncRNAs in CD14 monocytes from healthy volunteers. We investigated the regulation and function of an uncharacterized PA-induced lncRNA (PA-egulated nti-nflammatory ncRNA). We examined its role in inflammation resolution by employing knockdown and overexpression strategies in human and mouse macrophages. We also used RNA pulldown coupled with mass spectrometry to identify interacting nuclear proteins and their mechanistic involvement in functions in human macrophages.

Results: Treatment of human CD14 monocytes with PA-induced several lncRNAs and genes associated with inflammatory phenotype. PA strongly induced lncRNA expressed near . was also induced by cytokines and infectious agents in human monocytes/macrophages and was regulated by NF-κB (nuclear factor-kappa B). Time course studies showed was induced during inflammation resolution phase in PA-treated macrophages. knockdown with antisense oligonucleotides upregulated key inflammatory genes and vice versa with overexpression. We found that interacts with ELAVL1 (ELAV-like RNA-binding protein 1) protein via adenylate/uridylate-rich elements (AU-rich elements; AREs). ELAVL1 knockdown inhibited the anti-inflammatory functions of . Moreover, knockdown increased cytosolic localization of ELAVL1 and increased the stability of ARE-containing inflammatory genes. Mouse orthologous was downregulated in macrophages from mice with diabetes and atherosclerosis. overexpression attenuated proinflammatory genes in mouse macrophages.

Conclusions: Upregulation of under acute inflammatory conditions contributes to proresolution mechanisms via -ELAVL1 interactions. Conversely, downregulation in cardiometabolic diseases enhances ELAVL1 function and impairs inflammation resolution to further augment inflammation. Thus, inflammation-resolving lncRNAs like represent novel targets to combat inflammatory cardiometabolic diseases.