title: Circulating pathogen-associated molecular pattern - binding proteins and High Mobility Group Box protein 1 in nascent metabolic syndrome: implications for cellular Toll-like receptor activity.
abstract: OBJECTIVE
  The Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1).
  
  
  METHODS
  We measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n = 37) and healthy control subjects (n = 32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs).
  
  
  RESULTS
  Following adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR. In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α).
  
  
  CONCLUSIONS
  Thus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD.
authors: Laboratory for Atherosclerosis and Metabolic Research, Department of Pathology, Division of Endocrinology, Diabetes and Metabolism, University of California Davis Medical Center, Sacramento, CA, USA; VA Medical Center, Sacramento, CA, USA. Electronic address: ijialal@ucdavis.edu.
authors: I
authors: I
authors: Jialal
authors: Laboratory for Atherosclerosis and Metabolic Research, Department of Pathology, Division of Endocrinology, Diabetes and Metabolism, University of California Davis Medical Center, Sacramento, CA, USA.
authors: U
authors: U
authors: Rajamani
authors: Department of Clinical Sciences, Division of Biostatistics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: B
authors: B
authors: Adams-Huet
authors: Laboratory for Atherosclerosis and Metabolic Research, Department of Pathology, Division of Endocrinology, Diabetes and Metabolism, University of California Davis Medical Center, Sacramento, CA, USA.
authors: H
authors: H
authors: Kaur
mesh_terms: D000209:Acute-Phase Proteins; D000328:Adult; D000368:Aged; D001011:Aorta; D002352:Carrier Proteins / Q000097:blood*; D002478:Cells, Cultured; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D018950:Lipopolysaccharide Receptors / Q000097:blood*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D024821:Metabolic Syndrome / Q000097:blood*; D008875:Middle Aged; D016328:NF-kappa B / Q000097:blood; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000097:blood; D051193:Toll-Like Receptors / Q000502:physiology*; D055815:Young Adult; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein; C585491:HMGB1 protein, human; C495345:TLR4 protein, human
keywords: HMGB-1; Metabolic syndrome; PAMP-binding proteins; Toll-like receptors; sCD14