Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes

International Journal of Obesity volume 33, pages 519–524 (2009)Cite this article

Abstract

Objective:

The liver X receptors (LXRs) are ligand-activated nuclear transcription factors that have been shown to play major roles in lipid, glucose and cholesterol metabolism. Recently, members of the NR4A orphan nuclear receptor family have also been shown to regulate the expression of important genes in metabolically active tissues such as liver, adipose and skeletal muscle. Here, we investigated the role of LXRs to regulate the expression of the nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in adipocytes.

Approach:

White and brown adipose tissues from wild-type, LXRα−/−- and LXRα:β-deficient mice were collected from animals at room temperature or following cold exposure to measure NOR-1 mRNA. The expression of NOR-1 and its promoter activity in response to LXR ligands were determined in cultured primary brown adipocytes or mouse embryo fibroblasts derived from wild-type or LXRα−/− mice differentiated into adipocytes.

Results:

In LXRα−/−- and LXRα:β-deficient adipocytes, basal levels of NOR-1 were significantly reduced while retaining an equivalent proportional induction by β-adrenergic agonists. This reduced basal expression of NOR-1 in adipose tissue from LXR-deficient mice is a cell-autonomous event as it was also preserved in adipocytes differentiated from mouse embryo fibroblasts derived from these mice. In cultured primary brown adipocytes or cell lines, the expression of NOR-1 increased in response to an LXR agonist. A DNA sequence element (DR-4) capable of binding LXRs was found at −997 bp of the NOR-1 promoter, which was shown to be functional by promoter reporter gene activity, gel shift and chromatin immunoprecipitation assays.

Conclusion:

These data describe a new role for LXR to regulate NOR-1 gene expression in adipocytes and demonstrate that these two nuclear receptors have an interdependent regulatory relationship, in addition to each being involved in the control of metabolic fuel usage.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G et al. International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol Rev 2006; 58: 798–836.

    Article  CAS  Google Scholar 

  2. Katagiri Y, Hirata Y, Milbrandt J, Guroff G . Differential regulation of the transcriptional activity of the orphan nuclear receptor NGFI-B by membrane depolarization and nerve growth factor. J Biol Chem 1997; 272: 31278–31284.

    Article  CAS  Google Scholar 

  3. Williams GT, Lau LF . Activation of the inducible orphan receptor gene nur77 by serum growth factors: dissociation of immediate-early and delayed-early responses. Mol Cell Biol 1993; 13: 6124–6136.

    Article  CAS  Google Scholar 

  4. Borghaei RC, Sinai RS, Mochan E, Pease EA . Induction of mitogen-inducible nuclear orphan receptor by interleukin 1 in human synovial and gingival fibroblasts. Biochem Biophys Res Commun 1998; 251: 334–338.

    Article  CAS  Google Scholar 

  5. Fahrner TJ, Carroll SL, Milbrandt J . The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally. Mol Cell Biol 1990; 10: 6454–6459.

    Article  CAS  Google Scholar 

  6. Hazel TG, Nathans D, Lau LF . A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA 1988; 85: 8444–8448.

    Article  CAS  Google Scholar 

  7. Fu Y, Luo L, Luo N, Zhu X, Garvey WT . NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance. J Biol Chem 2007; 282: 31525–31533.

    Article  CAS  Google Scholar 

  8. Chao LC, Zhang Z, Pei L, Saito T, Tontonoz P, Pilch PF . Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. Mol Endocrinol 2007; 21: 2152–2163.

    Article  CAS  Google Scholar 

  9. Kumar N, Liu D, Wang H, Robidoux J, Collins S . Orphan nuclear receptor NOR-1 enhances 3′,5′-cyclic adenosine 5′-monophosphate-dependent uncoupling protein-1 gene transcription. Mol Endocrinol 2008; 22: 1057–1064.

    Article  CAS  Google Scholar 

  10. Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P . NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat Med 2006; 12: 1048–1055.

    Article  CAS  Google Scholar 

  11. Baker KD, Shewchuk LM, Kozlova T, Makishima M, Hassell A, Wisely B et al. The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell 2003; 113: 731–742.

    Article  CAS  Google Scholar 

  12. Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X et al. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 2003; 423: 555–560.

    Article  CAS  Google Scholar 

  13. Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA et al. Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways. Mol Endocrinol 2002; 16: 1638–1651.

    Article  CAS  Google Scholar 

  14. Maxwell MA, Cleasby ME, Harding A, Stark A, Cooney GJ, Muscat GE . Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. J Biol Chem 2005; 280: 12573–12584.

    Article  CAS  Google Scholar 

  15. Rius J, Martinez-Gonzalez J, Crespo J, Badimon L . Involvement of neuron-derived orphan receptor-1 (NOR-1) in LDL-induced mitogenic stimulus in vascular smooth muscle cells: role of CREB. Arterioscler Thromb Vasc Biol 2004; 24: 697–702.

    Article  CAS  Google Scholar 

  16. Kalaany NY, Mangelsdorf DJ . LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 2006; 68: 159–191.

    Article  CAS  Google Scholar 

  17. Nomiyama T, Bruemmer D . Liver X receptors as therapeutic targets in metabolism and atherosclerosis. Curr Atheroscler Rep 2008; 10: 88–95.

    Article  CAS  Google Scholar 

  18. Peet DJ, Janowski BA, Mangelsdorf DJ . The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev 1998; 8: 571–575.

    Article  CAS  Google Scholar 

  19. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ . LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995; 9: 1033–1045.

    Article  CAS  Google Scholar 

  20. Wang H, Zhang Y, Yehuda-Shnaidman E, Medvedev AV, Kumar N, Daniel KW et al. Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype. Mol Cell Biol 2008; 28: 2187–2200.

    Article  CAS  Google Scholar 

  21. Kalaany NY, Gauthier KC, Zavacki AM, Mammen PP, Kitazume T, Peterson JA et al. LXRs regulate the balance between fat storage and oxidation. Cell Metab 2005; 1: 231–244.

    Article  CAS  Google Scholar 

  22. Rehnmark S, Kopecky J, Jacobsson A, Nechad M, Herron D, Nelson BD et al. Brown adipocytes differentiated in vitro can express the gene for the uncoupling protein thermogenin: effects of hypothyroidism and norepinephrine. Exp Cell Res 1989; 182: 75–83.

    Article  CAS  Google Scholar 

  23. Blumberg B, Evans RM . Orphan nuclear receptors—new ligands and new possibilities. Genes Dev 1998; 12: 3149–3155.

    Article  CAS  Google Scholar 

  24. Maxwell MA, Muscat GE . The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 2006; 4: e002.

    Article  Google Scholar 

  25. Wingate AD, Arthur JS . Post-translational control of Nur77. Biochem Soc Trans 2006; 34: 1107–1109.

    Article  CAS  Google Scholar 

  26. Pearen MA, Myers SA, Raichur S, Ryall JG, Lynch GS, Muscat GE . The orphan nuclear receptor, NOR-1, a target of beta-adrenergic signaling, regulates gene expression that controls oxidative metabolism in skeletal muscle. Endocrinology 2008; 149: 2853–2865.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr David Mangelsdorf for providing wild-type and LXRα−/− and LXRα:β−/− mice.

Author information

Author notes

  1. N Kumar and H Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Translational Biology, Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA

    N Kumar, H Wang, D Liu & S Collins

  2. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    S Collins

Authors
  1. N Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Collins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, N., Wang, H., Liu, D. et al. Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes. Int J Obes 33, 519–524 (2009). https://doi.org/10.1038/ijo.2009.32

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2009.32

Keywords

This article is cited by

Search

Advanced search

Quick links