Advertisement

Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation

  • Eric E. Lloyd
    Affiliations
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
    Search for articles by this author
  • John W. Gaubatz
    Affiliations
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
    Search for articles by this author
  • Alan R. Burns
    Affiliations
    Section of Cardiovascular Sciences, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
    Search for articles by this author
  • Henry J. Pownall
    Correspondence
    Corresponding author. Tel.: +1 713 798 4160; fax: +1 713 798 9005.
    Affiliations
    Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, MS A-601, Baylor College of Medicine, 6565 Fannin St., Houston, TX 77030, United States
    Search for articles by this author

      Abstract

      Type 2 diabetes, a major risk factor for atherosclerosis, is associated with a cluster of lipid risk factors, many of which can be mechanistically linked with underlying dysregulated fatty acid metabolism and elevated plasma non-esterified fatty acids (NEFA). Thus, we tested the hypothesis that elevated NEFA dysregulates lipid metabolism at the levels of lipid synthesis and gene expression in THP-1 monocyte derived macrophages (MDM). THP-1 MDM incubated with oleic acid (OA) and a BODIPY-conjugated NEFA, accumulate, respectively, intracellular inclusions that are positive for oil red O and BODIPY-labeling. Parallel studies with [14C]OA show dose-dependent accumulation of intracellular 14C-labeled neutral lipid, almost exclusively as triglyceride; the rate of [3H]OA uptake increases as THP-1 MDM convert to foam cells. Preincubation of THP-1 MDM with higher concentrations of OA (1.8 mM versus 0.2 mM) was associated with enhanced uptake of Ac-LDL, and increased expression of adipocyte fatty acid binding protein, FAT/CD36, and cyclooxygenase-2 (COX-2); COX-2 mass and activity also increased. These observations suggest a mechanistic link between sustained elevations in albumin-bound NEFA and foam cell formation that may be mediated by enhanced adipogenesis, increased uptake of modified LDL, and upregulated formation of eicosanoids, which may be proinflammatory.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • McGarry J.D.
        Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.
        Diabetes. 2002; 51: 7-18
        • Lemieux I.
        Energy partitioning in gluteal-femoral fat: does the metabolic fate of triglycerides affect coronary heart disease risk?.
        Arterioscler Thromb Vasc Biol. 2004; 24: 795-797
        • Vilbergsson S.
        • Sigurdsson G.
        • Sigvaldason H.
        • et al.
        Coronary heart disease mortality amongst non-insulin-dependent diabetic subjects in Iceland: the independent effect of diabetes. The Reykjavik Study 17-year follow up.
        J Intern Med. 1998; 244: 309-316
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • et al.
        Protein measurement with the folin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Slayback J.R.
        • Cheung L.W.
        • Geyer R.P.
        Quantitative extraction of microgram amounts of lipid from cultured human cells.
        Anal Biochem. 1977; 83: 372-384
        • Folch J.
        • Lees M.
        • Sloane Stanley G.H.
        A simple method for the isolation and purification of total lipides from animal tissues.
        J Biol Chem. 1957; 226: 497-509
        • White T.
        • Bursten S.
        • Federighi D.
        • et al.
        High-resolution separation and quantification of neutral lipid and phospholipid species in mammalian cells and sera by multi-one-dimensional thin-layer chromatography.
        Anal Biochem. 1998; 258: 109-117
        • Shepherd J.
        • Bedford D.K.
        • Morgan H.G.
        Radioiodination of human low density lipoprotein: a comparison of four methods.
        Clin Chim Acta. 1976; 66: 97-109
        • Via D.P.
        • Dresel H.A.
        • Gotto Jr., A.M.
        Isolation and assay of the Ac-LDL receptor.
        Methods Enzymol. 1986; 129: 216-226
        • Roden M.
        • Price T.B.
        • Perseghin G.
        • et al.
        Mechanism of free fatty acid-induced insulin resistance in humans.
        J Clin Invest. 1996; 97: 2859-2865
        • Otto J.C.
        • DeWitt D.L.
        • Smith W.L.
        N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum.
        J Biol Chem. 1993; 268: 18234-18242
      1. Health, United States, 2004 with Chartbook on Trends in the Health of Americans, United States. U.S. Department of Health and Human Services, CDC, NCHS; 2004.

      2. Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 1998;158:1855–1867.

        • Randle P.J.
        • Garland P.B.
        • Hales C.N.
        • et al.
        The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.
        Lancet. 1963; 1: 785-789
        • Coe N.R.
        • Simpson M.A.
        • Bernlohr D.A.
        Targeted disruption of the adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels.
        J Lipid Res. 1999; 40: 967-972
        • Makowski L.
        • Boord J.B.
        • Maeda K.
        • et al.
        Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.
        Nat Med. 2001; 7: 699-705
        • Fu Y.
        • Luo N.
        • Lopes-Virella M.F.
        Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages.
        J Lipid Res. 2000; 41: 2017-2023
        • Miyaoka K.
        • Kuwasako T.
        • Hirano K.
        • Nozaki S.
        • Yamashita S.
        • Matsuzawa Y.
        CD36 deficiency associated with insulin resistance.
        Lancet. 2001; 357: 686-687
        • Febbraio M.
        • Abumrad N.A.
        • Hajjar D.P.
        • et al.
        A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism.
        J Biol Chem. 1999; 274: 19055-19062
        • Ibrahimi A.
        • Bonen A.
        • Blinn W.D.
        • et al.
        Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin.
        J Biol Chem. 1999; 274: 26761-26766
        • Vallve J.C.
        • Uliaque K.
        • Girona J.
        • et al.
        Unsaturated fatty acids and their oxidation products stimulate CD36 gene expression in human macrophages.
        Atherosclerosis. 2002; 164: 45-56
        • Patrignani P.
        Aspirin insensitive eicosanoid biosynthesis in cardiovascular disease.
        Thromb Res. 2003; 110: 281-286
        • Ohnaka K.
        • Numaguchi K.
        • Yamakawa T.
        • Inagami T.
        Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth muscle cells.
        Hypertension. 2000; 35: 68-75
        • Cipollone F.
        • Prontera C.
        • Pini B.
        • et al.
        Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability.
        Circulation. 2001; 104: 921-927
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans.
        Circulation. 2003; 107: 1479-1485
        • Patel R.N.
        • Attur M.G.
        • Dave M.N.
        • et al.
        A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production.
        J Immunol. 1999; 163: 3459-3467
        • Lee J.Y.
        • Sohn K.H.
        • Rhee S.H.
        • et al.
        Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4.
        J Biol Chem. 2001; 276: 16683-16689
        • Swislocki A.L.
        • Chen Y.D.
        • Golay A.
        • et al.
        Insulin suppression of plasma-free fatty acid concentration in normal individuals and patients with type 2 (non-insulin-dependent) diabetes.
        Diabetologia. 1987; 30: 622-626
        • Chung B.H.
        • Tallis G.A.
        • Cho B.H.
        • et al.
        Lipolysis-induced partitioning of free fatty acids to lipoproteins: effect on the biological properties of free fatty acids.
        J Lipid Res. 1995; 36: 1956-1970