Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha.

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Vanden Heuvel JP, Thompson JT, Frame SR, Gillies PJ

Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha.

Toxicol Sci. 2006 Aug;92(2):476-89. Epub 2006 May 26.

PubMed ID
16731579 [ View in PubMed
]
Abstract

Administration of ammonium salts of perfluorooctanoate (PFOA) to rats results in peroxisome proliferation and benign liver tumors, events associated with activation of the nuclear receptor (NR) peroxisome proliferator-activated receptor-alpha (PPARalpha). Due to its fatty acid structure, PFOA may activate other NRs, such as PPARbeta, PPARgamma, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPARalpha, PPARbeta, PPARgamma, LXRbeta, and RXRalpha by PFOA (including its linear and branched isomers) and perfluorooctane sulfonate (PFOS) was investigated and compared to several structural classes of natural fatty acids and appropriate positive control ligands. An NR ligand-binding domain/Gal4 DNA-binding domain chimeric reporter system was used. Human, mouse, and rat PPARalpha were activated by PFOA isomers and PFOS. PPARbeta was less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPARgamma, although the maximum induction of PPARgamma was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXRbeta nor the common heterodimerization partner RXRalpha was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPARalpha is the most likely target of PFOA and PFOS, although PPARgamma is also activated to some extent. Compared to naturally occurring long-chain fatty acids, e.g. linoleic and alpha-linolenic acids, these perfluorinated fatty acid analogs were more selective and less potent in their activation of the NRs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
alpha-Linolenic acidPeroxisome proliferator-activated receptor alphaProteinHumans
Unknown
Not AvailableDetails
alpha-Linolenic acidPeroxisome proliferator-activated receptor deltaProteinHumans
Unknown
Not AvailableDetails
alpha-Linolenic acidPeroxisome proliferator-activated receptor gammaProteinHumans
Unknown
Not AvailableDetails
alpha-Linolenic acidRetinoic acid receptor RXR-alphaProteinHumans
Unknown
Not AvailableDetails
Caprylic acidPeroxisome proliferator-activated receptor alphaProteinHumans
Unknown
Not AvailableDetails
CiprofibratePeroxisome proliferator-activated receptor alphaProteinHumans
Unknown
Not AvailableDetails
Oleic AcidPeroxisome proliferator-activated receptor alphaProteinHumans
Unknown
Not AvailableDetails
Oleic AcidPeroxisome proliferator-activated receptor deltaProteinHumans
Unknown
Not AvailableDetails
Oleic AcidRetinoic acid receptor RXR-alphaProteinHumans
Unknown
Not AvailableDetails