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Identification of Activator Hormone for Hepatic Orphan Nuclear Receptor

Investigators
Biel, Merrill; Weinberger, Cary
Institutions
DHHS/NIH - National Institute of Environmental Health Sciences
Start date
2000
End date
2000
Objective
Not Available.
More information
Summary of Work: FXR is a rat nuclear receptor that activates transcription in response to metabolites of farnesyl diphosphate. Since these farnesoids are juvenile hormone (JH) agonists, it was postulated that FXR may be related to an insect JH receptor. This hypothesis is now supported by the findings that FXR is induced by plant-derived and synthetic JH agonists and specifically regulated by the JH antagonist precocene which induces premature metamorphosis. Precocene, like benzo[a]pyrene, is a rodent hepatocarcinogen and both were metabolized by mouse liver microsomes to FXR antagonists. In contrast, a precocene dimer and tetrahydrochrysene analogs induced FXR. Structure-activity studies next led to the identification of 3 alpha-hydroxysteroids and bile acids as endogenous FXR effectors.

Even though some mevalonate-derived product is required for DNA synthesis and cell growth, farnesoids induce apoptosis and suppress HMG CoA reductase enzyme activity at the post-transcriptional level. The cholesterol-lowering agent SR-12813 similarly inhibits reductase and now joins farnesol as an FXR activator which provides a potential link between this receptor and control in the mevalonate pathway. Finally, a diverse group of xenobiotic FXR inducers including natural and synthetic insecticides has been discerned whose effects on cell growth are proposed to hinge on their abilities to perturb these isoprenoid regulatory mechanisms.

Funding Source
Nat'l. Inst. of Environmental Health Sciences
Project number
Z01ES70072-07
Categories
Pesticide Residues