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



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.



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.



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.
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA. Electronic address: weiyang.zhang@va.gov.
Wei-Yang
WY
Zhang
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA.
Daniel A
DA
Franco
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA.
Eric
E
Schwartz
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA.
Karen
K
D'Souza
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA.
Sheetal
S
Karnick
Department of Medicine, Phoenix VA Healthcare System, Phoenix, AZ 85012, USA.
Peter D
PD
Reaven
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000099221:Protein Kinase C zeta
D051700:Activating Transcription Factor 3; D000893:Anti-Inflammatory Agents; D002518:Ceramides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D020928:Mitogen-Activated Protein Kinases; D019308:Palmitic Acid; D058539:Phosphatidylinositol 3-Kinase; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta; C490449:ATF3 protein, human
ATF3; Cell signaling; HDL; Inflammation; MAP kinase; Saturated fatty acid