Advertisement

Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells

      Abstract

      Objective

      Elevated levels of nonesterified fatty acids (NEFA) in obesity and type 2 diabetes may contribute to the development of atherosclerosis. Therefore, we examined whether NEFA could regulate expression of scavenger receptors responsible for uptake of oxidized LDL (oxLDL) in macrophages, a critical step in atherogenesis.

      Methods and results

      Expression level of scavenger receptors in NEFA-treated macrophage-like THP-1 and Raw264.7 cells were analyzed by real-time PCR. Palmitic acid showed the greatest enhancement of expression of lectin-like oxidized LDL receptor (LOX-1) among 7 NEFA examined (4 saturated and 3 unsaturated fatty acids). Upregulation of LOX-1 was selective as increases in expression level of other scavenger receptors (CD36, SR-AI, SR-BI, and CD68) were not observed. Western blotting analysis indicated that upregulation of LOX-1 also occurred at the protein level. Uptake of oxLDL by Raw264.7 cells was promoted by palmitic acid, and the enhanced uptake was abrogated when the cells were transfected with siRNA against LOX-1. Downregulation of Toll-like receptor (TLR) 2, TLR4, or IRAK4 with siRNA did not prevent LOX-1 upregulation, whereas inhibitors of p38 MAPK (p38) and reactive oxygen species (ROS) signal inhibited the upregulation of LOX-1 induced by palmitic acid.

      Conclusions

      These results suggest that elevated level of palmitic acid may contribute to development of atherosclerosis through enhanced uptake of oxLDL via upregulation of LOX-1 in macrophages. The effects of palmitic acid may be mediated by ROS-p38 pathway rather than TLRs.

      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

        • Pilz S.
        • Scharnagl H.
        • Tiran B.
        • et al.
        Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease.
        J Clin Endocrinol Metab. 2006; 91: 2542-2547
        • Steinberg H.O.
        • Tarshoby M.
        • Monestel R.
        • et al.
        Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.
        J Clin Invest. 1997; 100: 1230-1239
        • Wang X.L.
        • Zhang L.
        • Youker K.
        • et al.
        Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.
        Diabetes. 2006; 55: 2301-2310
        • Zhang W.Y.
        • Schwartz E.
        • Wang Y.
        • et al.
        Elevated concentrations of nonesterified fatty acids increase monocyte expression of CD11b and adhesion to endothelial cells.
        Arterioscler Thromb Vasc Biol. 2006; 26: 514-519
        • Shi H.
        • Kokoeva M.V.
        • Inouye K.
        • et al.
        TLR4 links innate immunity and fatty acid-induced insulin resistance.
        J Clin Invest. 2006; 116: 3015-3025
        • Murphy J.E.
        • Tedbury P.R.
        • Homer-Vanniasinkam S.
        • et al.
        Biochemistry and cell biology of mammalian scavenger receptors.
        Atherosclerosis. 2005; 182: 1-15
        • 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
        • Moriwaki H.
        • Kume N.
        • Sawamura T.
        • et al.
        Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1541-1547
        • Daviet L.
        • McGregor J.L.
        Vascular biology of CD36: roles of this new adhesion molecule family in different disease states.
        Thromb Haemost. 1997; 78: 65-69
        • Febbraio M.
        • Podrez E.A.
        • Smith J.D.
        • et al.
        Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
        J Clin Invest. 2000; 105: 1049-1056
        • Kataoka H.
        • Kume N.
        • Miyamoto S.
        • et al.
        Expression of lectin like oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions.
        Circulation. 1999; 99: 3110-3117
        • Mehta J.L.
        • Sanada N.
        • Hu C.P.
        • et al.
        Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet.
        Circ Res. 2007; 100: 1634-1642
        • Li L.
        • Sawamura T.
        • Renier G.
        Glucose enhances human macrophage LOX-1 expression: role for LOX-1 in glucose-induced macrophage foam cell formation.
        Circ Res. 2004; 94: 892-901
        • Smirnova I.V.
        • Kajstura M.
        • Sawamura T.
        • et al.
        Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation.
        Am J Physiol Heart Circ Physiol. 2004; 287: H782-H790
        • Coll T.
        • Jove M.
        • Rodriguez-Calvo R.
        • et al.
        Palmitate-mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation.
        Diabetes. 2006; 55: 2779-2787
        • Haversen L.
        • Danielsson K.N.
        • Fogelstrand L.
        • et al.
        Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages.
        Atherosclerosis. 2009; 202: 382-393
        • Moriwaki H.
        • Kume N.
        • Kataoka H.
        • et al.
        Expression of lectin-like oxidized low density lipoprotein receptor-1 in human and murine macrophages: upregulated expression by TNF-alpha.
        FEBS Lett. 1998; 440: 29-32
        • Ciapaite J.
        • Bakker S.J.
        • Diamant M.
        • et al.
        Metabolic control of mitochondrial properties by adenine nucleotide translocator determines palmitoyl-CoA effects. Implications for a mechanism linking obesity and type 2 diabetes.
        JFEBS J. 2006; 273: 5288-5302
        • Staiger H.
        • Staiger K.
        • Stefan N.
        • et al.
        Palmitate-induced interleukin-6 expression in human coronary artery endothelial cells.
        Diabetes. 2004; 53: 3209-3216
        • van Wijk J.P.
        • de Koning E.J.
        • Castro Cabezas M.
        • et al.
        Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes.
        Diabetes Care. 2005; 28: 844-849
        • Maingrette F.
        • Renier G.
        Linoleic acid increases lectin-like oxidized LDL receptor-1 (LOX-1) expression in human aortic endothelial cells.
        Diabetes. 2005; 54: 1506-1513
        • Brinkley T.E.
        • Kume N.
        • Mitsuoka H.
        • et al.
        Elevated soluble lectin-like oxidized LDL receptor-1 (sLOX-1) levels in obese postmenopausal women.
        Obesity (Silver Spring). 2008; 16: 1454-1456
        • Shiu S.W.
        • Tan K.C.
        • Wong Y.
        • et al.
        Glycoxidized LDL increases lectin-like oxidized low density lipoprotein receptor-1 in diabetes mellitus.
        Atherosclerosis. 2009; 203: 522-527
        • Dominguez J.H.
        • Mehta J.L.
        • Li D.
        • et al.
        Anti-LOX-1 therapy in rats with diabetes and dyslipidemia: ablation of renal vascular and epithelial manifestations.
        Am J Physiol Renal Physiol. 2008; 294: F110-F119
        • Chen M.
        • Masaki T.
        • Sawamura T
        LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis.
        Pharmacol Ther. 2002; 95: 89-100
        • Kunjathoor V.V.
        • Febbraio M.
        • Podrez E.A.
        • et al.
        Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.
        J Biol Chem. 2002; 277: 49982-49988
        • Chen M.
        • Kakutani M.
        • Minami M.
        • et al.
        Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1107-1115
        • Fisker Hag A.M.
        • Pedersen S.F.
        • Kjaer A.
        Gene expression of LOX-1, VCAM-1, and ICAM-1 in pre-atherosclerotic mice.
        Biochem Biophys Res Commun. 2008; 377: 689-693
        • Mehta J.L.
        • Chen J.
        • Hermonat P.L.
        • et al.
        Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders.
        Cardiovasc Res. 2006; 69: 36-45
        • Li D.
        • Liu L.
        • Chen H.
        • et al.
        LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells.
        Circulation. 2003; 107: 612-617
        • Cominacini L.
        • Pasini A.F.
        • Garbin U.
        • et al.
        Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species.
        J Biol Chem. 2000; 275: 12633-12638
        • Schaeffer D.F.
        • Riazy M.
        • Parhar K.S.
        • et al.
        LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma.
        J Lipid Res. 2009; 50: 1676-1684
        • Mukai E.
        • Kume N.
        • Hayashida K.
        • et al.
        Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized LDL receptor-1 in vascular smooth muscle cells.
        Atherosclerosis. 2004; 176: 289-296
        • Lee J.G.
        • Lim E.J.
        • Park D.W.
        • et al.
        A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation.
        Cell Signal. 2008; 20: 2266-2275
        • McCubrey J.A.
        • Lahair M.M.
        • Franklin RA
        Reactive oxygen species-induced activation of the MAP kinase signaling pathways.
        Antioxid Redox Signal. 2006; 8: 1775-1789
        • Lambertucci R.H.
        • Hirabara S.M.
        • Silveira Ldos R.
        • et al.
        Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells.
        J Cell Physiol. 2008; 216: 796-804