title: Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response may initially be protective, but when prolonged, have been implicated in atherogenesis in diabetic conditions. Triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to ER stress. We sought to evaluate the effect of acute FFA elevation on ER stress in endothelial and circulating white cells.
  
  
  RESULTS
  Twenty-one healthy subjects were treated with intralipid (20%; 45 mL/h) plus heparin (12 U/kg/h) infusion for 5 hours. Along with increased triglyceride and FFA levels, intralipid/heparin infusion reduced the calf reactive hyperemic response without a change in conduit artery flow-mediated dilation consistent with microvascular dysfunction. To investigate the short-term effects of elevated triglycerides and FFA, we measured markers of ER stress in peripheral blood mononuclear cells (PBMCs) and vascular endothelial cells (VECs). In VECs, activating transcription factor 6 (ATF6) and phospho-inositol requiring kinase 1 (pIRE1) proteins were elevated after infusion (both P<0.05). In PBMCs, ATF6 and spliced X-box-binding protein 1 (XBP-1) gene expression increased by 2.0- and 2.5-fold, respectively (both P<0.05), whereas CHOP and GADD34 decreased by ≈67% and 74%, respectively (both P<0.01). ATF6 and pIRE1 protein levels also increased (both P<0.05), and confocal microscopy revealed the nuclear localization of ATF6 after infusion, suggesting activation.
  
  
  CONCLUSIONS
  Along with microvascular dysfunction, intralipid infusion induced an early protective ER stress response evidenced by activation of ATF6 and IRE1 in both leukocytes and endothelial cells. Our results suggest a potential link between metabolic disturbances and ER stress that may be relevant to vascular disease.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (E.T.).
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Tampakakis
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Corey E
authors.initials: CE
authors.lastname: Tabit
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Monika
authors.initials: M
authors.lastname: Holbrook
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Erika A
authors.initials: EA
authors.lastname: Linder
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Brittany D
authors.initials: BD
authors.lastname: Berk
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Frame
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Rosa
authors.initials: R
authors.lastname: Bretón-Romero
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fetterman
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Noyan
authors.initials: N
authors.lastname: Gokce
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vita
authors.affiliation: Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (C.E.T., M.H., E.A.L., B.D.B., A.A.F., R.B.R., J.L.F., N.G., J.A.V., N.M.H.).
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage; D015415:Biomarkers / Q000378:metabolism; D004655:Emulsions / Q000008:administration & dosage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D064368:Healthy Volunteers; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D006940:Hyperemia / Q000503:physiopathology; D007262:Infusions, Intravenous; D007866:Leg / Q000098:blood supply*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010743:Phospholipids / Q000008:administration & dosage* / Q000097:blood; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013024:Soybean Oil / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000925:Anticoagulants; D015415:Biomarkers; C497249:DDIT3 protein, human; D004655:Emulsions; D010743:Phospholipids; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C545823:soybean oil, phospholipid emulsion; D051742:Transcription Factor CHOP; D013024:Soybean Oil; D006493:Heparin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: endoplasmic reticulum stress; endothelium; free fatty acids; leukocyte