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HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway

      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.

      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.

      Keywords

      Abbreviations:

      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)
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