title: GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS.
abstract: OBJECTIVE
  Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms.
  
  
  METHODS
  Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated.
  
  
  RESULTS
  G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post-transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation.
  
  
  CONCLUSIONS
  PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase.
authors: Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Zhongyang
authors: Z
authors: Lu
authors: Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Yanchun
authors: Y
authors: Li
authors: Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, People's Republic of China.
authors: Junfei
authors: J
authors: Jin
authors: Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Xiaoming
authors: X
authors: Zhang
authors: Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
authors: Yusuf A
authors: YA
authors: Hannun
authors: Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA; Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: huangyan@musc.edu.
authors: Yan
authors: Y
authors: Huang
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C473034:FFAR1 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D013109:Sphingomyelins; D019308:Palmitic Acid; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase
keywords: Atherosclerosis; Endothelium; LPS; Palmitic acid; Sphingolipid