HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway. (April 2017)

• Record Type: Journal Article
• Authors: Zhang, Wei-Yang; Franco, Daniel A.; Schwartz, Eric; D'Souza, Karen; Karnick, Sheetal; Reaven, Peter D.
• Is Part Of: Atherosclerosis. Volume 259(2017)
• Page Start: 83
• Page End: 96
• Publication Date: 2017-04
• Subjects: Saturated fatty acid -- HDL -- Inflammation -- Cell signaling -- MAP kinase -- ATF3; LPS lipopolysaccharide -- TLRs Toll-like receptors -- PA palmitic acid -- HAECs human aortic endothelial cells -- MAPKs mitogen-activated protein kinases -- PI3K Phosphoinositide 3-kinase -- PKC protein kinase C -- NF-κB nuclear factor kappa B -- JNK N-terminal kinase -- ERK extracellular-signal-regulated kinase -- MβCD methyl-beta-cyclodextrin -- 2-OhβCD 2-hydroxy-beta-cyclodextrin -- pPCR quantitative real-time PCR -- IL-6 interleukin 6 -- IL-8 interleukin 8 -- IL-1β interleukin 1 beta -- MIP-1α macrophage inflammatory protein 1 alpha -- DAMPs damage-associated molecular pattern molecules -- ATF3 activating transcription factor 3 -- CEBP CCAAT/ enhancer binding protein; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.09.003
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. Methods: Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. Results: Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-ζ, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. Conclusions: These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation. Highlights: Palmitic acid augments inflammation via ceramide formation and MAPK activation in endothelial cells. Activation of ATF3 appears to be a critical downstream pro-inflammatory transcription factor. High density lipoprotein (HDL) inhibits palmitic acid and lipopolysaccharide (LPS) induced inflammation. Protection by HDL is mediated by Akt activity and reduction of ATF3.