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Activation of testicular orphan receptor 4 by fatty acids

Nien-Pei Tsai1, Mostaqul Huq, Pawan Gupta

  • 1Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455-0217, USA.

Biochimica Et Biophysica Acta
|October 6, 2009
PubMed

Insights

Natural fatty acids activate the testicular orphan receptor 4 (TR4), a nuclear receptor. Gamma-linoleic acid specifically enhances TR4

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear receptors regulate gene expression in response to various stimuli.
  • Orphan nuclear receptors, like TR4, have poorly defined functions and ligands.
  • Lipids and fatty acids are critical signaling molecules in cellular processes.

Purpose of the Study:

  • To identify natural compounds that activate the mouse orphan nuclear receptor TR4.
  • To investigate the specific effects of gamma-linoleic acid on TR4 activity and downstream gene expression.
  • To explore the potential physiological role of TR4 in lipid sensing.

Main Methods:

  • Bioassay-guided screening of mouse tissue extracts.
  • In vitro transactivation assays using TR4.
  • Analysis of downstream gene expression (ApoE, PEPCK) and coregulator interactions.
  • Comparative analysis with other nuclear receptors (PPARs).

Main Results:

  • Natural fatty acids, particularly gamma-linoleic acid, were identified as activators of mouse TR4.
  • Gamma-linoleic acid specifically enhanced TR4-mediated transactivation, promoting ApoE and PEPCK expression.
  • Gamma-linoleic acid induced TR4 interaction with coregulators RIP140 and PCAF.
  • TR4 activation by gamma-linoleic acid was found to be specific and distinct from PPAR-mediated regulation.

Conclusions:

  • The testicular orphan receptor 4 (TR4) can be activated by specific fatty acids, suggesting a role in lipid sensing.
  • Gamma-linoleic acid is a TR4-specific modulator, influencing the expression of key metabolic genes.
  • Understanding TR4-ligand interactions provides insights into its physiological functions and potential therapeutic targets.

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