Skip to main content
SpringerLink
Log in

Identification of fatty acid methyl ester as naturally occurring transcriptional regulators of the members of the peroxisome proliferator-activated receptor family

  • Article
  • Published:
Lipids

Abstract

The nuclear hormone receptors NUC-1 (PPARξ) and PPARα are members of the peroxisome proliferator-activated receptor (PPAR) family. The members of this receptor family are activated by agents that stimulate peroxisome proliferation, free fatty acids, prostaglandin J2 metabolites, and agents considered for the therapy of insulin-independent diabetes mellitus. To identify putative physiological agents that activate NUC-1, we tested the ability of acetone extracts of various rat tissues to activate the transcription of an MMTV-luciferase reporter gene, via a GR/NUC-1 hybrid receptor. GR/NUC-1 contains the ligand binding region of the NUC-1 receptor and the DNA binding domain of the glucocorticoid receptor. Using this assay, we found stimulatory activity in the pancreas, which upon purification and characterization was identified as methylpalmitate, known to be enriched in pancreatic lipids. In addition, we determined that ethyl esters of palmitic and oleic acids are also potent activators of this receptor. thus, fatty acid ester formation may control the cellular concentrations of fatty acids, and acyl-ester formation may play a role in the control of metabolic pathways and the activation of the PPAR.

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

Similar content being viewed by others

Abbreviations

DMSO:

dimethylsulfoxide

GR:

glucocorticoid receptor

HPLC:

ligh-performance liquid chromatography

NMR:

muclear magnetic resonance

PPAR:

peroxisome proliferator-activated receptor

PPRE:

PPAR hormone response element

UV:

ultraviolet

WY:

14643, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio)acetic acid

References

  1. Issemann, I., and Green, S. (1990) Activation of a Member of the Steroid Hormone Receptor Superfamily by Peroxisome Proliferators [see comments],Nature 347, 645–650.

    Article  PubMed  CAS  Google Scholar 

  2. Schmidt, A., Endo, N., Rutledge, S.J., Vogel, R., Shinar, D., and Rodan, G.A. (1992) Identification of a New Member of the Steroid Hormone Receptor Superfamily That Is Activated by a Peroxisome Proliferator and Fatty Acids,Mol. Endocrinol. 6, 1634–1641.

    Article  PubMed  CAS  Google Scholar 

  3. Zhu, Y., Alvares, K., Huang, Q., Rao, M.S., and Reddy, J.K. (1993) Cloning of a New Member of the Peroxisome Proliferator-Activated Receptor Gene Family from Mouse Liver,J. Biol. Chem. 268, 26817–26820.

    PubMed  CAS  Google Scholar 

  4. Dreyer, C., Krey, G., Keller, H., Givel, F., Helftenbein, G., and Wahli, W. (1992) Control of the Peroxisomal Beta-Oxidation Pathway by a Novel Family of Nuclear Hormone Receptors,Cell 68, 879–887.

    Article  PubMed  CAS  Google Scholar 

  5. Kliewer, S.A., Forman, B.M., Blumberg, B., Ong, E.S., Borgmeyer, U., Mangelsdorf, D.J., Umesono, K., and Evans, R.M. (1994) Differential Expression and Activation of a Family of Murine Peroxisome Proliferator-Activated Receptors,Proc. Natl. Acad. Sci. USA 91, 7355–7359.

    Article  PubMed  CAS  Google Scholar 

  6. Gottlicher, M., Widmark, E., Li, Q., and Gustafsson, J.A. (1992) Fatty Acids Activate a Chimera of the Clofibric Acid-Activated Receptor and the Glucocorticoid Receptor,Proc. Natl. Acad. Sci. USA 89, 4653–4657.

    Article  PubMed  CAS  Google Scholar 

  7. Dreyer, C., Keller, H., Mahfoudi, A., Laudet, V., Krey, G., and Wahli, W. (1993) Positive Regulation of the Peroxisomal Beta-Oxidation Pathway by Fatty Acids Through Activation of Peroxisome Proliferator-Activated Receptors (PPAR),Biol. Cell 77, 67–76.

    Article  PubMed  CAS  Google Scholar 

  8. Boie, Y., Adam, M., Rushmore, T.H., and Kennedy, B.P. (1993) Enantioselective Activation of the Peroxisome Proliferator-Activated Receptor,J. Biol. Chem. 268, 5530–5534.

    PubMed  CAS  Google Scholar 

  9. Sher, T., Yi, H.F., McBride, O.W., and Gonzalez, F.J. (1993) cDna Cloning, Chromosomal Mapping, and Functional Characterization of the Human Peroxisome Proliferator Activated Receptor,Biochemistry 32, 5598–5604.

    Article  PubMed  CAS  Google Scholar 

  10. Chawla, A., Schwarz, E.J., Dimaculangan, D.D., and Lazar, M.A. (1994) Peroxisome Proliferator-Activated Receptor (PPAR) Gamma: Adipose-Predominant Expression and Induction Early in Adipocyte Differentiation,Endocrinology 135, 798–800.

    Article  PubMed  CAS  Google Scholar 

  11. Tontonoz, P., Hu, E., and Spiegelman, B.M. (1994) Stimulation of Adipogenesis in Fibroblasts by PPAR Gamma 2, A Lipid-Activated Transcription Factor [published erratum appears inCell 1995 Mar 24;80(6): following 957],Cell 79, 1147–1156.

    Article  PubMed  CAS  Google Scholar 

  12. Forman, B.M., Tontonoz, P., Chen, J., Brun, R.P., Spiegelman, B.M., and Evans, R.M. (1995) 15-Deoxy-Delta 12, 14-Prostaglandin J2 Is a Ligand for the Adipocyte Determination Factor PPAR Gamma,Cell 83, 803–812.

    Article  PubMed  CAS  Google Scholar 

  13. Kliewer, S.A., Lenhard, J.M., Willson, T.M., Patel, I., Morris, D.C., and Lehmann, J.M. (1995) A Prostaglandin J2 Metabolite Binds Peroxisome Proliferator-Activated Receptor Gamma and Promotes Adipocyte Differentiation,Cell 83, 813–819.

    Article  PubMed  CAS  Google Scholar 

  14. Ibrahimi, A., Teboul, L., Gaillard, D., Amri, E.Z., Ailhaud, G., Young, P., Cawthorne, M.A., and Grimaldi, P.A. (1994) Evidence for a Common Mechanism of Action for Fatty Acids and Thiazolidinedione Antidiabetic Agents on Gene Expression in Preadipose Cells,Mol. Pharmacol. 46, 1070–1076.

    PubMed  CAS  Google Scholar 

  15. Shinar, D.M., Endo, N., Rutledge, S.J., Vogel, R., Rodan, G.A., and Schmidt, A. (1994) NER, A New Member of the Gene Family Encoding the Human Steroid Hormone Nuclear Receptor,Gene 147, 273–276.

    Article  PubMed  CAS  Google Scholar 

  16. Green, S., and Chambon, P. (1987) Oestradiol Induction of a Glucocorticoid-Responsive Gene by a Chimaeric Receptor,Nature 325, 75–78.

    Article  PubMed  CAS  Google Scholar 

  17. Danielsen, M., Northrop, J.P., and Ringold, G.M. (1986) The Mouse Glucocorticoid Receptor: Mapping of Functional Domains by Cloning, Sequencing and Expression of Wild-Type and Mutant Receptor Proteins,Embo. J. 5, 2513–2522.

    PubMed  CAS  Google Scholar 

  18. Webster, N.J., Green, S., Jin, J.R., and Chambon, P. (1988) The Hormone-Binding Domains of the Estrogen and Glucocorticoid Receptors Contain an Inducible Transcription Activation Function,Cell 54, 199–207.

    Article  PubMed  CAS  Google Scholar 

  19. Tugwood, J.D., Issemann, I., Anderson, R.G., Bundell, K.R., McPheat, W.L., and Green, S. (1992) The Mouse Peroxisome Proliferator Activated Receptor Recognizes a Response Element in the 5′ Flanking Sequence of the Rat Acyl CoA Oxidase Gene,Embo. J. 11, 433–439.

    PubMed  CAS  Google Scholar 

  20. Dhopeshwarkar, G.A., and Mead, J.F. (1962) Evidence for Occurrence of Methyl Esters in Body and Blood Lipids,Proc. Soc. Exp. Biol. Med. 109, 425–429.

    PubMed  CAS  Google Scholar 

  21. Leikola, E., Nieminen, E., and Salomaa, E. (1965) Occurrence of Methyl Esters in the Pancreas,J. Lipid. Res. 6, 490–493.

    PubMed  CAS  Google Scholar 

  22. Lough, A.K., and Garton, G.A. (1968) The Lipids of Human Pancreas with Special Reference to the Presence of Fatty Acid Methyl Esters,Lipids 3, 321–323.

    CAS  PubMed  Google Scholar 

  23. Kloog, Y., Zatz, M., Rivnay, B., Dudley, P.A., and Markey, S.P. (1982) Nonpolar Lipid Methylation-Identification of Nonpolar Methylated Products Synthesized by Rat Basophilic Leukemia Cells, Retina and Parotid,Biochem. Pharmacol. 31, 753–759.

    Article  PubMed  CAS  Google Scholar 

  24. Engelsen, S.J., and Zatz, M. (1982) Stimulation of Fatty Acid Methylation in Human Red Cell Membranes by Phospholipase A2 Activation,Biochim. Biophys. Acta 711, 515–520.

    PubMed  CAS  Google Scholar 

  25. Zatz, M., Dudley, P.A., Kloog, Y., and Markey, S.P. (1981) Nonpolar Lipid Methylation. Biosynthesis of Fatty Acid Methyl Esters by Rat Lung Membranes Using S-Adenosylmethionine,J. Biol. Chem. 256, 10028–10032.

    PubMed  CAS  Google Scholar 

  26. Yoshida, S., Tamura, T., Tamura, M., Takeshita, M., Terao, H., Fujioka, T., and Itoga, T. (1984) Evidence for the Presence of Fatty Acid Methyl Esters in Human Hepatoma Tissue from a Patient with Hypercholesterolemia,J. Appl. Biochem. 6, 314–318.

    PubMed  CAS  Google Scholar 

  27. Spector, A.A., and Soboroff, J.M. (1972) Long-Chain Fatty Acid Methyl Ester Hydrolase Activity in Mammalian Cells,Lipids 7, 186–190.

    PubMed  CAS  Google Scholar 

  28. Bora, P.S., Spilburg, C.A., and Lange, L.G. (1989) Identification of a Satellite Fatty Acid Ethyl Ester Synthase from Human Myocardium as a Glutathione S-Transferase,J. Clin. Invest. 84, 1942–1946.

    Article  PubMed  CAS  Google Scholar 

  29. Manautou, J.E., and Carlson, G.P. (1991) Ethanol-Induced Fatty Acid Ethyl Ester formationIn Vivo andIn Vitro in Rat Lung,Toxicology 70, 303–312.

    Article  PubMed  CAS  Google Scholar 

  30. Hamamoto, T., Yamada, S., Murawaki, Y., and Kawasaki, H. (1991) Effect of Ethanol Feeding on Fatty Acid Ethyl Ester Synthase Activity in the Liver and Pancreas of Rats Fed a Nutritionally Adequate Diet or a Low Protein Diet,Biochem. Pharmacol. 42, 1148–1150.

    Article  PubMed  CAS  Google Scholar 

  31. Bora, P.S., Wu, X., Spilburg, C.A., and Lange, L.G. (1992) Furification and Characterization of Fatty Acid Ethyl Ester Synthase-II from Human Myocardium,J. Biol. Chem. 267, 13217–13221.

    PubMed  CAS  Google Scholar 

  32. Bora, P.S., Bora, N.S., Wu, X.L., and Lange, L.G. (1991) Molecular Cloning, Sequencing, and Expression of Human Myocardial Fatty Acid Ethyl Ester Synthase-III cDNA,J. Biol. Chem. 266, 16774–16777.

    PubMed  CAS  Google Scholar 

  33. Sharma, R., Gupta, S., Singhal, S.S., Ahmad, H., Haque, A., and Awasthi, Y.C. (1991) Independent Segregation of Glutathione S-Transferase and Fatty Acid Ethyl Ester Synthase from Pancreas and Other Human Tissues,Biochem. J. 275, 507–513.

    PubMed  CAS  Google Scholar 

  34. Singhal, S.S., Gupta, S., Saxena, M., Sharma, R., Ahmad, H., Ansari, G.A., and Awasthi, Y.C. (1991) Purification and Characterization of Glutathione S-Transferases from Rat Pancreas,Biochim. Biophys. Acta 1079, 285–292.

    PubMed  CAS  Google Scholar 

  35. Warnotte, C., Gilon, P., Nenquin, M., and Henquin, J.C. (1994) Mechanisms of the Stimulation of Insulin Release by Saturated Fatty Acids. A Study of Palmitate Effects in Mouse Beta-Cells,Diabetes 43, 703–711.

    PubMed  CAS  Google Scholar 

  36. Banner, C.D., Gottlicher, M., Widmark, E., Sjovall, J., Rafter, J.J., and Gustafsson, J.A. (1993) A Systematic Analytical Chemistry/Cell Assay Approach to Isolate Activators of Orphan Nuclear Receptors from Biological Extracts: Characterization of Peroxisome Proliferator-Activated Receptor Activators in Plasma,J. Lipid. Res. 34, 1583–1591.

    PubMed  CAS  Google Scholar 

  37. Al Tuwaijri, A., Akdamar, K., and Di Luzio, N.R. (1981) Modification of Galactosamine-Induced Liver Injury in Rats by Reticuloendothelial System Stimulation or Depression,Hepatology 1, 107–113.

    Google Scholar 

  38. Lindert, K.A., Caldwell Kenkel, J.C., Nukina, S., Lemasters, J.J., and Thurman, R.G. (1992) Activation of Kupffer Cells on Reperfusion Following Hypoxia: particle Phagocytosis in a Low-Flow, Reflow Model,Am. J. Physiol. 262, G345–350.

    PubMed  CAS  Google Scholar 

  39. Marzi, I., Cowper, K., Takei, Y., Lindert, K., Lemasters, J.J., and Thurman, R.G. (1991) Methyl Palmitate Prevents Kupffer Cell Activation and Improves Survival After Orthotopic Liver Transplantation in the Rat,Transpl. Int. 4, 215–220.

    Article  PubMed  CAS  Google Scholar 

  40. Imamura, T., Takata, I., Ogasawara, M., Matsutani, Y., Yamamoto, T., and Asagami, C. (1991) [Clofibrate Treatment of Psoriasis with Hypertriglycemia—Clinical, Histological and Laboratory Analysis],Nippon Hifuka Gakkai Zasshi 101, 623–628.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, 19486, West Point, Pennsylvania

    Azriel Schmidt, Robert L. Vogel, Su Jane Rutledge & Gideon A. Rodan

  2. Department of Medicinal Chemistry, Merck Research Laboratories, 19486, West Point, Pennsylvania

    Keith M. Witherup & Steven M. Pitzenberger

  3. Molecular Biology, Merck Frosst Centre for Therapeutic Research, H9R 4P8, Point Claire-Dorval, Quebec, Canada

    Mohammed Adam

Authors
  1. Azriel Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert L. Vogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keith M. Witherup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Su Jane Rutledge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven M. Pitzenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammed Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gideon A. Rodan
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Schmidt, A., Vogel, R.L., Witherup, K.M. et al. Identification of fatty acid methyl ester as naturally occurring transcriptional regulators of the members of the peroxisome proliferator-activated receptor family. Lipids 31, 1115–1124 (1996). https://doi.org/10.1007/BF02524285

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02524285

Keywords

Search

Navigation