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Visfatin induces cholesterol accumulation in macrophages through up-regulation of scavenger receptor-A and CD36

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Cell Stress and Chaperones Aims and scope

Abstract

As a new potential inflammatory mediator, visfatin plays an important role in inflammation and atherosclerosis. The formation of macrophage-derived foam cells occurs at the early stage of atherosclerosis and underlies the visible fatty streak. Recent studies have indicated that visfatin may be associated with the development of foam cells, but its exact effect and molecular mechanism remain unknown. This study aims to study the effect of visfatin on foamy cell formation and its underlying molecular mechanism. Visfatin levels were determined in apolipoprotein E (ApoE) knockout (KO) mice on a western diet for 16 weeks. Effects of visfatin in cholesterol accumulation were studied both in vivo and in vitro. The levels of scavenger receptors located in macrophage surface were measured in RAW264.7 cells after treatment with visfatin. Visfatin levels were much higher in ApoE KO mice than that in the control mice. Meanwhile, oxidized low-density lipoprotein induces both visfatin release from RAW264.7 cells and its cellular levels within 24 h. Visfatin promotes lipid accumulation mainly through excessive cholesterol uptake not only in RAW264.7 cells but also in peritoneal macrophages isolated from ApoE KO mice. Furthermore, visfatin induces the activation of scavenger receptors (SR)-A and cluster of differentiation (CD)36, but not that of SR-BI, ATP-binding cassette transporter (ABC)A1, or ABCG1 in RAW264.7 cells. Both transcriptional and posttranscriptional regulation may work in concert to mediate the expression of SR-A and CD36 in visfatin-treated cells. Visfatin induces cholesterol accumulation in macrophages and accelerates the process of atherosclerosis mainly through modulating the expression of SR-A and CD36.

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Reference

  • Berliner JA, Heinecke JW (1996) The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 20:707–727

    Article  PubMed  CAS  Google Scholar 

  • Castagna A, Polati P, Bossi AM, Girelli D (2012) Monocyte/macrophage proteomics: recent findings and biomedical applications. Expert Rev Proteom 9:201–215

    Article  CAS  Google Scholar 

  • Chen X, Zhang H, McAfee S, Zhang C (2010) The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice. Am J Physiol Heart Circ Physiol 299:605–612

    Article  Google Scholar 

  • Chen CY, Shyue SK, Ching LC, Su KH, Wu YL, Kou YR et al (2011) Wogonin promotes cholesterol efflux by increasing protein phosphatase 2B-dependent dephosphorylation at ATP-binding cassette transporter-A1 in macrophages. J Nutr Biochem 22:1015–1021

    Article  PubMed  CAS  Google Scholar 

  • Cheng LC, Su KH, Kou YR, Shyue SK, Ching LC, Yu YB et al (2011) α-Lipoic acid ameliorates foam cell formation via liver X receptor α-dependent upregulation of ATP-binding cassette transporters A1 and G1. Free Radic Biol Med 50:47–54

    Article  PubMed  CAS  Google Scholar 

  • Collot-Teixeira S, Martin J, McDermott-Roe C, Poston R, McGregor JL (2007) CD36 and macrophages in atherosclerosis. Cardiovasc Res 75:468–477

    Article  PubMed  CAS  Google Scholar 

  • Dahl TB, Yndestad A, Skjelland M, Øie E, Dahl A, Michelsen A et al (2007) Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115:972–980

    Article  PubMed  CAS  Google Scholar 

  • Dahl T, Ranheim T, Holm S, Berge R, Aukrust P, Halvorsen P (2011) Nicotinamide phosphoribosyltransferase and lipid accumulation in macrophages. Eur J Clin Invest 41:1098–1104

    Article  PubMed  CAS  Google Scholar 

  • De Luis DA, Gonzalez Sagrado M, Conde R, Aller R, Izaola O, Romero E (2008) Effect of a hypocaloric diet on serum visfatin in obese non-diabetic patients. Nutrition 24:517–521

    Article  PubMed  Google Scholar 

  • Glass CK, Witztum JL (2001) Atherosclerosis: the road ahead. Cell 104:503–516

    Article  PubMed  CAS  Google Scholar 

  • Ji A, Meyer JM, Cai L, Akinmusire A, Akinmusire A, de Beer MC et al (2011) Scavenger receptor SR-BI in macrophage lipid metabolism. Atherosclerosis 217:106–112

    Article  PubMed  CAS  Google Scholar 

  • Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD et al (2004) Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental experimental inflammation and clinical sepsis. J Clin Invest 113:1318–1327

    PubMed  CAS  Google Scholar 

  • Kamari Y, Shaish A, Shemesh S, Vax E, Grosskopfl I, Dotan S et al (2011) Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-e-deficient mice lacking bone marrow-derived interleukin-1alpha. Biochem Biophys Res Commun 405:197–203

    Article  PubMed  CAS  Google Scholar 

  • Kjerrulf M, Berke Z, Aspegen A, Umaerus M, Nilsson T, Svensson L et al (2006) Reduced cholesterol accumulation by leptin deficient (ob/ob) mouse macrophages. Inflamm Res 55:300–309

    Article  PubMed  CAS  Google Scholar 

  • Kleemann R, Zadelaar S, Kooistra T (2008) Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 79:360–376

    Article  PubMed  CAS  Google Scholar 

  • Kopff B, Jegier A (2005) Adipokines: adiponectin, leptin, resistin and coronary heart disease risk. Przegl Lek 62:69–72

    PubMed  Google Scholar 

  • Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S et al (2002) 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 277:49982–49988

    Article  PubMed  CAS  Google Scholar 

  • Li AC, Glass CK (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8:1235–1242

    Article  PubMed  CAS  Google Scholar 

  • Li K, Yao WQ, Zheng XD, Liao K (2009) Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage. Cell Res 19:1006–1017

    Article  PubMed  CAS  Google Scholar 

  • Liu SW, Qiao SB, Yuan JS, Liu DQ (2009) Association of plasma visfatin levels with inflammation, atherosclerosis and acute coronary syndromes (ACS) in humans. Clin Endocrinol (Oxf) 71:202–207

    Article  CAS  Google Scholar 

  • Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  PubMed  CAS  Google Scholar 

  • Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R (1994) ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140

    Article  PubMed  CAS  Google Scholar 

  • Nowell MA, Richards PJ, Fielding CA, Ognjanovic S, Topley N, Williams AS et al (2006) Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum 54:2084–2095

    Article  PubMed  CAS  Google Scholar 

  • Out R, Hoekstra M, Hildebrand RB, Kruit JK, Meurs I, Li ZS et al (2006) Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 26:2295–2300

    Article  PubMed  CAS  Google Scholar 

  • Paschou P, Kukuvitis A, Yavropoulou MP, Dritsoula A, Giapoutzidis V, Anastasiou O et al (2010) Genetic variation in the visfatin (PBEF1/NAMPT) gene and type 2 diabetes in the Greek population. Cytokine 51:25–27

    Article  PubMed  CAS  Google Scholar 

  • Plump AS, Smith JD, Hayek T, Aalto-Setӓlӓ K, Walsh A, Verstuyft JG et al (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343–353

    Article  PubMed  CAS  Google Scholar 

  • Rahaman SO, Lennon DJ, Febbraio M, Podrez EA, Hazen SL, Silverstein RL (2006) A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab 4:211–221

    Article  PubMed  CAS  Google Scholar 

  • Ross R (1999) Atherosclerosis-an inflammatory disease. N Eng J Med 340:115–126

    Article  CAS  Google Scholar 

  • Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 14:1431–1437

    PubMed  CAS  Google Scholar 

  • Sethi JK, Vidal-Puig A (2005) Visfatin: the missing link between intra-abdominal obesity and diabetes? Trends Mol Med 11:344–347

    Article  PubMed  CAS  Google Scholar 

  • Spiroglou SG, Kostopoulos CG, Varakis JN, Papadaki HH (2010) Adipokines in periaortic and epicardial adipose tissue: differential expression and relation to atherosclerosis. J Atheroscler Thromb 17:115–130

    Article  PubMed  CAS  Google Scholar 

  • Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK (1995) T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci 92:3893–3897

    Article  PubMed  CAS  Google Scholar 

  • Takahashi N, Kawada T, Goto T, Kim CS, Taimatsu A, Eqawa K et al (2003) Abietic acid activates peroxisome proliferator-activated receptor-gamma (PPARgamma) in RAW264.7 cells and 3 T3-L1 adipocytes to regulate gene expression involved in inflammation and lipid metabolism. FEBS Lett 550:190–194

    Article  PubMed  CAS  Google Scholar 

  • Tsai JY, Su KH, Shyue SK, Kou YR, Yu YB, Hsiao SH et al (2010) EGb761 ameliorates the formation of foam cells by regulating the expression of SR-A and ABCA1: role of haem oxygenase-1. Cardiovasc Res 88:415–423

    Article  PubMed  CAS  Google Scholar 

  • Van Eck M, De Winther MP, Herijgers N, Havekes LM, Hofker MH, Groot PH et al (2000) Effect of human scavenger receptor class A overexpression in bone marrow-derived cells on cholesterol levels and atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 20:2600–2606

    Article  PubMed  Google Scholar 

  • Van Eck M, Bos IST, Hildebrand RB, Van Rij BT, Van Berkel TJC (2004) Dual role for scavenger receptor class B, type I on bone marrow-derived cells in atherosclerotic lesion development. Am J Pathol 165:785–794

    Article  PubMed  Google Scholar 

  • Wang N, Silver DL, Thiele C, Tall AR (2001) ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem 276:23742–23747

    Article  PubMed  CAS  Google Scholar 

  • Wu H, Moulton KS, Glass CK (1992) Macrophage scavenger receptors and atherosclerosis. Trends Cardiovasc Med 2:220–225

    Article  PubMed  CAS  Google Scholar 

  • Xie C, Kang J, Chen JR, Lazarenko OP, Ferguson ME, Badger TM et al (2011) Lowbush blueberries inhibit scavenger receptors CD36 and SR-A expression and attenuate foam cell formation in ApoE-deficient mice. Food Funct 2:588–594

    Article  PubMed  CAS  Google Scholar 

  • Yan JJ, Tang NP, Tang JJ, Jia EZ, Wang MW, Wang QM et al (2010) Genetic variant in visfatin gene promoter is associated with decreased risk of coronary artery disease in a Chinese population. Clin Chim Acta 411:26–30

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Yu Xie for excellent technical assistance. This project was supported by grants from the National Natural Sciences Foundation of China (no. 81072776) and Guangdong 211 key disciplines construction project.

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The authors declare that there is no conflict of interests.

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Authors and Affiliations

  1. Department of Traditional Chinese Medicine, Nan fang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China

    Fenghua Zhou, Yunyun Pan, Yuhua Jia, Xiaoshan Zhao, Qiang Wan & Xiaobing Cui

  2. School of Traditional Chinese Medicine, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China

    Fenghua Zhou, Yunyun Pan, Yuhua Jia, Xiaoshan Zhao, Yuyao Chen, Jianxin Diao, Qiang Wan & Xiaobing Cui

  3. People’s Liberation Army Air Force Radar Academy, 288 Huangpu Street, Wuhan, 430019, Hubei, China

    Zhiyong Huang

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  1. Fenghua Zhou
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  2. Yunyun Pan
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  3. Zhiyong Huang
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  4. Yuhua Jia
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Correspondence to Yuhua Jia.

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Fenghua Zhou and Yunyun Pan equally contributed to this work.

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Zhou, F., Pan, Y., Huang, Z. et al. Visfatin induces cholesterol accumulation in macrophages through up-regulation of scavenger receptor-A and CD36. Cell Stress and Chaperones 18, 643–652 (2013). https://doi.org/10.1007/s12192-013-0417-z

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  • DOI: https://doi.org/10.1007/s12192-013-0417-z

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