Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors

Article metrics

Abstract

PEROXISOMES are cytoplasmic organelles which are important in mammals in modulation of lipid homeostasis, including the metabolism of long-chain fatty acids and conversion of cholesterol to bile salts (reviewed in refs 1 and 2). Amphipathic carboxylates such as clofibric acid have been used in man as hypolipidaemic agents and in rodents they stimulate the proliferation of peroxisomes. These agents, termed peroxisome proliferators, and all-trans retinoic acid activate genes involved in peroxisomal-mediated β-oxidation of fatty acids1–4. Here we show that the receptor activated by peroxisome proliferators5 and the retinoid X receptor-α (ref. 6) form a heterodimer that activates acyl-CoA oxidase gene expression in response to either clofibric acid or the retinoid X receptor-α ligand, 9-cis retinoic acid, an all-trans retinoic acid metabolite7,8; simultaneous exposure to both activators results in a synergistic induction of gene expression. These data demonstrate the coupling of the peroxisome proliferator and retinoid signalling pathways and provide evidence for a physiological role for 9-cis retinoic acid in modulating lipid metabolism.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Lazarow, P. B. & Fujiki, Y. A. Rev. Cell Biol. 1, 489–530 (1985).

  2. 2

    Vamecq, J. & Draye, J. P. Essays Biochem. 24, 115–225 (1989).

  3. 3

    Reddy, J. K. & Lalwani, N. D. Crit. Rev. Toxicol. 12, 1–58 (1983).

  4. 4

    Hertz, R. & Bar-Tana, J. Biochem. J. 281, 41–43 (1992).

  5. 5

    Isseman, I. & Green, S. Nature 347, 645–650 (1990).

  6. 6

    Mangelsdorf, D. J., Ong, E. S., Dyck, J. A. & Evans, R. M. Nature 345, 224–229 (1990).

  7. 7

    Heyman, R. A. et al. Cell 68, 397–406 (1992).

  8. 8

    Levin, A. A. et al. Nature 355, 359–361 (1992).

  9. 9

    Osumi, T., Wen, J.-K. & Hashimoto, T. Biochem. biophys. Res. Commun. 175, 866–871 (1991).

  10. 10

    Tugwood, J. D. et al. EMBO J. 11, 433–439 (1992).

  11. 11

    Dreyer, C. et al. Cell 68, 879–887 (1992).

  12. 12

    Mangelsdorf, D. J. et al. Cell 66, 555–561 (1991).

  13. 13

    Kliewer, S. A. et al. Proc. natn. Acad. Sci. U.S.A. 89, 1448–1452 (1992).

  14. 14

    Kliewer, S. A., Umesono, K., Mangelsdorf, D. J. & Evans, R. M. Nature 355, 446–449 (1992).

  15. 15

    Yu, V. C. et al. Cell 67, 1251–1266 (1991).

  16. 16

    Leid, M. et al. Cell 68, 377–395 (1992).

  17. 17

    Zhang, X.-k. et al. Nature 355, 441–446 (1992).

  18. 18

    Umesono, K., Murakami, K. K., Thompson, C. C. & Evans, R. M. Cell 65, 1255–1266 (1991).

  19. 19

    Hijikata, M. et al. J. biol. Chem. 265, 4600–4606 (1990).

  20. 20

    Nemali, M. R. et al. Cancer Res. 48, 5316–5324 (1988).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.