Skip to main content
SpringerLink
Log in

Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The liver X receptors (LXRα and LXRβ), ligand-activated transcription factors, belong to the superfamily of nuclear hormone receptors and have been shown to play a major role in atherosclerosis by modulating cholesterol and triglyceride metabolism. In this report, we describe a novel LXR target, the adipocyte fatty acid binding protein (aP2), which plays an important role in fatty acid metabolism, adipocyte differentiation and atherosclerosis. While LXR agonists induce aP2 mRNA expression in human monocytes (THP-1 cells) and macrophages in a time- and concentration-dependent manner, they have no effect on aP2 expression in human adipocytes. The increase in aP2 mRNA level was additive when THP-1 cells were treated with LXR and PPARγ agonists. Also, an RXR agonist induced aP2 expression in these cells. While no additive effect was observed with LXR and RXR agonists, additive effects were observed with RXR and PPARγ agonists. GW9662, a potent PPARγ antagonist, inhibited PPARγ-induced aP2 expression without affecting LXR-mediated aP2 expression indicating the induction is mediated directly through LXR activation. Analysis of human aP2 promoter revealed a potential LXR response element (LXRE). Gel shift data showed that the LXRα/RXRα heterodimer bound to the LXRE motif in aP2 promoter in vitro in a sequence-specific manner. Deletion and mutation analyses of the proximal aP2 promoter confirm that this is a functional LXRE. These data indicate for the first time that human macrophage aP2 promoter is a direct target for the regulation by LXR/RXR heterodimers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Glatz JF, van der Vusse GJ (1996) Cellular fatty acid binding proteins: their function and physiological significance. Prog Lipid Res 35:243–282

    Article  PubMed  CAS  Google Scholar 

  2. Cae NR, Bernlohr DA (1998) Physiological properties and functions of intracellular fatty acid binding proteins. Biochim Biophys Acta 1391:287–306

    Google Scholar 

  3. Spiegelman BM, Frank M, Green H (1983) Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for gelycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem 258:10083–10089

    PubMed  CAS  Google Scholar 

  4. Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM (1986) Adipocyte P2 gene: developmental expression and homology of 5′-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci USA 83:3786–3790

    Article  PubMed  CAS  Google Scholar 

  5. Amri E-Z, Bertrand B, Aihaud G, Grimaldi P (1991) Regulation of adipose cell defferentiation. I. Fatty acids are inducers of the aP2 gene expression. J. Lipid Res 32:1449–1456

    PubMed  CAS  Google Scholar 

  6. Distel RJ, Robinson GS, Spiegelman BM (1992) Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. J Biol Chem 267:5937–5941

    PubMed  CAS  Google Scholar 

  7. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Speiegelman BM (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274:1377–1379

    Article  PubMed  CAS  Google Scholar 

  8. Boord JB, Fazio S, Linton MF (2002) Cytoplasmic fatty acid binding proteins: emerging roles in metabolism and atherosclerosis. Curr Opin Lipidol 13:141–147

    Article  PubMed  CAS  Google Scholar 

  9. Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF (2001) Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Med 7(6):699–705

    Article  PubMed  CAS  Google Scholar 

  10. Lu TT, Rapa JJ, Mangelsdorf DJ (2001) Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J Biol Chem 276:37735–37738

    PubMed  CAS  Google Scholar 

  11. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272(6):3137–3140

    Article  PubMed  CAS  Google Scholar 

  12. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ (2001) Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem 276(46):43018–24

    Article  PubMed  CAS  Google Scholar 

  13. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ (2000) Regulation of absorption, ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289(5484):1524–1529

    Article  PubMed  CAS  Google Scholar 

  14. Whitney KD, Watson MA, Goodwin B, Galard CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA (2001) Liver X receptor (LXR) regulation of the LXRα gene in human macrophages. J Biol Chem 276:43509–43515

    Article  PubMed  CAS  Google Scholar 

  15. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P (2001) Autoregulation of the human liver X receptor alpha promoter. Mol Cell Biol 21:7558–7568

    Article  PubMed  CAS  Google Scholar 

  16. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14(22):2819–2830

    Article  PubMed  CAS  Google Scholar 

  17. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (2000) Role of LXRs in control of lipogenesis. Genes Dev 14(22):2831–2838

    Article  PubMed  CAS  Google Scholar 

  18. Kim JB, Spiegelman BM (1996) ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10(9):1096–1107

    Article  PubMed  CAS  Google Scholar 

  19. Seo JB, Moon HM, Kim WS, Lee YS, Jeong HW, Yoo EJ, Ham J, Kang H, Park MG, Steffensen KR, Stulnig TM, Gustafsson JA, Park SD, Kim JB (2004) Activated liver X receptors stimulate adipocyte differentiation through induction of peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol 24(8):3430–3444

    Article  PubMed  CAS  Google Scholar 

  20. Spencer TA, Li D, Russel JS, Collins JL, Bledsoe RK, Consler TG, Moore LB, Galardi CM, McKee DD, Moore JT, Watson MA, Parks DJ, Lambert MH, Willson TM (2001) Pharmacophore analysis of the nuclear oxysterol receptor LXRa. J Med Chem 44:886–897

    Article  PubMed  CAS  Google Scholar 

  21. Pelton PD, Zhou L, Demarest KT, Burris TP (1999) PPARg activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochem Biophys Res Commun 261:456–458

    Article  PubMed  CAS  Google Scholar 

  22. Burris TP, Pelton PD, Zhou L, Osborne MC, Cryan E, Demarest KT (1999) A novel method for analysis of nuclear receptor function at natural promoters: peroxisome proliferator-activated receptor gamma agonist actions on aP2 gene expression detected using branched DNA messenger RNA quantitation. Mol Endocrinol 13(3):410–417

    Article  PubMed  CAS  Google Scholar 

  23. Edwards PA, Kennedy MA, Mak PA (2002) LXRs; Oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. Vascul Pharmacol 38:249–256

    Article  PubMed  CAS  Google Scholar 

  24. Fu Y, Luo N, Lopes-Virella M (2000) Osidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J Lipid Res 41:2017–2023

    PubMed  CAS  Google Scholar 

  25. Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS (2002) Adipocyte fatty acid binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolimia. Arterioscler Thromb Vasc Biol 22:1686–1691

    Article  PubMed  CAS  Google Scholar 

  26. Yoshikawa T, Shinano H, Amemiva-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga JI, Harada K, Gotoda T, Kimura S, Ishivashi S, Yamada N (2001) Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element binding protein 1c gene promoter. Mol Cell Biol 21:2991–3000

    Article  PubMed  CAS  Google Scholar 

  27. Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F (2002) Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277(37):34182–34190

    Article  PubMed  CAS  Google Scholar 

  28. Fan C, Yan J, Qian Y, Wo X, Gao L (2006) Regulation of lipoprotein lipase expression by effect of hawthorn flavonoids on peroxisome proliferator response element pathway. J Pharmacol Sci 100:51–58

    Article  PubMed  CAS  Google Scholar 

  29. Juvet LK, Andresen SM, Schuster GU, Dalen KT, Tobin KA, Hollung K, Haugen F, Jacinto S, Ulven SM, Bamberg K, Gustafsson JA, Nebb HI (2003) On the role of liver × receptors in lipid accumulation in adipocytes. Mol Endocrinol 17(2):172–182

    Article  PubMed  CAS  Google Scholar 

  30. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (2001) A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7(1):161–171

    Article  PubMed  CAS  Google Scholar 

  31. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4(4):611–617

    Article  PubMed  CAS  Google Scholar 

  32. Park KS, Ciaraldi TP, Lindgren K, Abrams-Carter L, Mudaliar S, Nikoulina SE, Tufari SR, Veerkamp JH, Vidal-Puig A, Henry RR (1998) Troglitazone effects on gene expression in human skeletal muscle of type II diabetes involve up-regulation of peroxisome proliferator-activated receptor-gamma. J Clin Endocrinol Metab 83(8):2830–2835

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular and Metabolic Research, Wyeth Research, N-2275, 500 Arcola Rd., Collegeville, PA, 19426, USA

    Qiang-Yuan Liu, Elaine Quinet & Ponnal Nambi

Authors
  1. Qiang-Yuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elaine Quinet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ponnal Nambi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ponnal Nambi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, QY., Quinet, E. & Nambi, P. Adipocyte fatty acid-binding protein (aP2), a newly identified LXR target gene, is induced by LXR agonists in human THP-1 cells. Mol Cell Biochem 302, 203–213 (2007). https://doi.org/10.1007/s11010-007-9442-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-007-9442-5

Keywords

Search

Navigation