Pro-atherogenic proteoglycanase ADAMTS-1 is down-regulated by lauric acid through PI3K and JNK signaling pathways in THP-1 derived macrophages

  • Melissa-Hui-Ling Ong
  • Hong-Kin Wong
  • Tengku-Sifzizul Tengku-Muhammad
  • Quok-Cheong Choo
  • Choy-Hoong ChewEmail author
Original Article


The prevalence of atherosclerosis has increased significantly in the recent years due to sedentary lifestyle and high-fat diet. However, the association between saturated fat intake and the increased risk for atherosclerotic cardiovascular diseases remains heavily debated. Lauric acid belongs to the saturated fatty acid group and its unique medium chain fatty acid properties are proven to be beneficial to humans in many ways. Thus, the aim of this project is to investigate the effect of lauric acid on the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes—ADAMTS-1, ADAMTS-4, and ADAMTS-5—in macrophages. These genes encode for proteases that participate in the extracellular matrix remodeling and they play important roles in the vulnerability of atherosclerotic plaque. Here, we show that the treatment of 20 µM of lauric acid successfully reduced both transcriptional and translational expressions of these genes in THP-1 differentiated macrophages after 24-h incubation. Further cell signaling experiments using a panel of kinase inhibitors and phosphorylated antibodies proved that lauric acid down-regulated ADAMTS-1 by reducing the activation of PI3K and JNK at Tyr458 and Tyr185, respectively. Finally, JNK1 siRNA knockdown assay confirmed that ADAMTS-1 was regulated through JNK pathway, and lauric acid interfered with this pathway to down-regulate ADAMTS-1 expression. Although preliminary, this present study indicates that lauric acid has the potential to stabilize atherosclerotic plaque and may prevent thrombosis by interfering with the ADAMTS-1 expression through PI3K/JNK pathways.


ADAMTS Atherosclerosis JNK Lauric acid PI3K 



This work was supported by Malaysia’s Ministry of Higher Education’s Fundamental Research Grant Scheme (FRGS) (FRGS/2/2013/SKK01/UTAR/02/3).


  1. 1.
    Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126CrossRefGoogle Scholar
  2. 2.
    Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519CrossRefGoogle Scholar
  3. 3.
    Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8:802–815CrossRefGoogle Scholar
  4. 4.
    Lusis AJ (2000) Atherosclerosis. Nature 407:233–241CrossRefGoogle Scholar
  5. 5.
    Crowther MA (2000) Pathogenesis of atherosclerosis. Hematology 2005:436–441CrossRefGoogle Scholar
  6. 6.
    WHO (2015) Malaysia: WHO statistical profile. World Health Organization. Accessed 18 June 2017
  7. 7.
    Gerrity RG, Naito HK, Richardson M et al (1979) Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am J Pathol 95:775–792Google Scholar
  8. 8.
    Koenen RR, Weber C (2010) Therapeutic targeting of chemokine interactions in atherosclerosis. Nat Rev Drug Discov 9:141–153CrossRefGoogle Scholar
  9. 9.
    Uday Kumar D, Christopher V, Sobarani D et al (2014) Lauric acid as potential natural product in the treatment of cardiovascular disease: a review. J Bioanal Biomed 6:37–39Google Scholar
  10. 10.
    Lindeberg S, Lundh B (1993) Apparent absence of stroke and ischaemic heart disease in a traditional Melanesian island: a clinical study in Kitava. J Intern Med 233:269–275CrossRefGoogle Scholar
  11. 11.
    The American Oil Chemists’ Society (2017) Palm kernel and coconut (Lauric) oils. AOCS Lipid Library. Accessed 28 June 2017
  12. 12.
    Mensink RP, Zock PL, Kester ADM et al (2003) Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 77:1146–1155CrossRefGoogle Scholar
  13. 13.
    Temme EH, Mensink RP, Hornstra G (1996) Comparison of the effects of diets enriched in lauric, palmitic, or oleic acids on serum lipids and lipoproteins in healthy women and men. Am J Clin Nutr 63:897–903CrossRefGoogle Scholar
  14. 14.
    Thijssen MA, Mensink RP (2005) Fatty acids and atherosclerotic risk. Handb Exp Pharmacol 170:165–194CrossRefGoogle Scholar
  15. 15.
    Wågsäter D, Björk H, Zhu C et al (2008) ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 196:514–522CrossRefGoogle Scholar
  16. 16.
    Lee CW, Hwang I, Park C-S et al (2011) Comparison of ADAMTS-1, -4 and -5 expression in culprit plaques between acute myocardial infarction and stable angina. J Clin Pathol 64:399–404CrossRefGoogle Scholar
  17. 17.
    Bongrazio M, Baumann C, Zakrzewicz A et al (2000) Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress. Cardiovasc Res 47:384–393CrossRefGoogle Scholar
  18. 18.
    Norata G, Björk H, Hamsten A et al (2004) High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-α in human endothelial cells. Matrix Biol 22:557–560CrossRefGoogle Scholar
  19. 19.
    Kumar S, Chen M, Li Y et al (2016) Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE–/– mice. Sci Rep 6:31133CrossRefGoogle Scholar
  20. 20.
    Didangelos A, Mayr U, Monaco C et al (2012) Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis. J Biol Chem 287:19341–19345CrossRefGoogle Scholar
  21. 21.
    ATCC (2016) THP-1 ATCC® TIB-202™. ATCC. Accessed 1 June 2017
  22. 22.
    Daigneault M, Preston JA, Marriott HM et al (2010) The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte-derived macrophages. PLoS ONE 5:e8668CrossRefGoogle Scholar
  23. 23.
    Lim WS, Ng DL, Kor SB et al (2013) Tumour necrosis factor alpha down-regulates the expression of peroxisome proliferator activated receptor alpha (PPARα) in human hepatocarcinoma HepG2 cells by activation of NF-κB pathway. Cytokine 61:266–274CrossRefGoogle Scholar
  24. 24.
    Aranda PS, LaJoie DM, Jorcyk CL (2012) Bleach gel: a simple agarose gel for analyzing RNA quality. Electrophoresis 33:366–369CrossRefGoogle Scholar
  25. 25.
    Ashlin TG, Kwan APL, Ramji DP (2013) Regulation of ADAMTS-1, -4 and -5 expression in human macrophages: differential regulation by key cytokines implicated in atherosclerosis and novel synergism between TL1A and IL-17. Cytokine 64:234–242CrossRefGoogle Scholar
  26. 26.
    Calabrese EJ, Baldwin LA (2001) Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol Sci 22:285–291CrossRefGoogle Scholar
  27. 27.
    Calabrese EJ, Baldwin LA (2003) Chemotherapeutics and hormesis. Crit Rev Toxicol 33:305–353CrossRefGoogle Scholar
  28. 28.
    Calabrese EJ, Staudenmayer JW, Stanek EJ, Hoffmann GR (2006) Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database. Toxicol Sci 94:368–378CrossRefGoogle Scholar
  29. 29.
    Calabrese EJ, Stanek EJ, Nascarella MA, Hoffmann GR (2008) Hormesis predicts low-dose responses better than threshold models. Int J Toxicol 27:369–378CrossRefGoogle Scholar
  30. 30.
    Southam CM, Ehrlich J (1943) Effects of extract of western red-cedar heartwood on certain wooddecaying fungi in culture. Phytopathology 33:517–524Google Scholar
  31. 31.
    Naito S, Shiomi T, Okada A et al (2007) Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int 57:703–711CrossRefGoogle Scholar
  32. 32.
    Bondeson J, Wainwright S, Hughes C et al (2008) The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 26:139–145Google Scholar
  33. 33.
    Lee Y, Thompson JT, de Lera AR et al (2009) Isomer-specific effects of conjugated linoleic acid on gene expression in RAW 264.7. J Nutr Biochem 20:848–859CrossRefGoogle Scholar
  34. 34.
    Reiss K, Cornelsen I, Husmann M et al (2011) Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. J Biol Chem 286:26931–26942CrossRefGoogle Scholar
  35. 35.
    Zainal Z, Longman AJ, Hurst S et al (2009) Modification of palm oil for anti-inflammatory nutraceutical properties. Lipids 44:581–592CrossRefGoogle Scholar
  36. 36.
    Curtis CL, Rees SG, Little CB et al (2002) Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids. Arthritis Rheum 46:1544–1553CrossRefGoogle Scholar
  37. 37.
    Ross-Jones TN, McIlwraith CW, Kisiday JD et al (2016) Influence of an n-3 long-chain polyunsaturated fatty acid-enriched diet on experimentally induced synovitis in horses. J Anim Physiol Anim Nutr (Berl) 100:565–577CrossRefGoogle Scholar
  38. 38.
    Richards JS, Russell DL, Ochsner S et al (2002) Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization. Recent Prog Horm Res 57:195–220CrossRefGoogle Scholar
  39. 39.
    Le Bras GF, Taylor C, Koumangoye RB et al (2015) TGFβ loss activates ADAMTS-1-mediated EGF-dependent invasion in a model of esophageal cell invasion. Exp Cell Res 330:29–42CrossRefGoogle Scholar
  40. 40.
    Miller AL, Garza AS, Johnson BH et al (2007) Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells. Cancer Cell Int 7:3CrossRefGoogle Scholar
  41. 41.
    Gerits N, Kostenko S, Shiryaev A et al (2008) Relations between the mitogen-activated protein kinase and the cAMP-dependent protein kinase pathways: comradeship and hostility. Cell Signal 20:1592–1607CrossRefGoogle Scholar
  42. 42.
    Wang H-H, Hsieh H-L, Yang C-M (2010) Calmodulin kinase II-dependent transactivation of PDGF receptors mediates astrocytic MMP-9 expression and cell motility induced by lipoteichoic acid. J Neuroinflammation 7:84CrossRefGoogle Scholar
  43. 43.
    Vares G, Sai S, Wang B et al (2015) Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. Cancer Lett 362:167–173CrossRefGoogle Scholar
  44. 44.
    Ozaki I, Hamajima H, Matsuhashi S et al (2011) Regulation of TGF-β1-induced pro-apoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver. Front Physiol 2:78CrossRefGoogle Scholar
  45. 45.
    Malhi H, Bronk SF, Werneburg NW et al (2006) Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 281:12093–12101CrossRefGoogle Scholar
  46. 46.
    Solinas G, Naugler W, Galimi F et al (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci 103:16454–16459CrossRefGoogle Scholar
  47. 47.
    Nguyen MTA, Satoh H, Favelyukis S et al (2005) JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 280:35361–35371CrossRefGoogle Scholar
  48. 48.
    Couplan E, Le Cann M, Le Foll C et al (2009) Polyunsaturated fatty acids inhibit PI3K activity in a yeast-based model system. Biotechnol J 4:1190–1197CrossRefGoogle Scholar
  49. 49.
    Yin Y, Sui C, Meng F et al (2017) The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K/Akt pathway. Lipids Health Dis 16:87CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Melissa-Hui-Ling Ong
    • 1
  • Hong-Kin Wong
    • 1
  • Tengku-Sifzizul Tengku-Muhammad
    • 2
  • Quok-Cheong Choo
    • 3
  • Choy-Hoong Chew
    • 1
    Email author
  1. 1.Department of Biomedical Science, Faculty of ScienceUniversiti Tunku Abdul RahmanKamparMalaysia
  2. 2.Institute of Marine BiotechnologyUniversiti Malaysia TerengganuKuala NerusMalaysia
  3. 3.Department of Biological Science, Faculty of ScienceUniversiti Tunku Abdul RahmanKamparMalaysia

Personalised recommendations