Peroxisome proliferator-activated receptor human response

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Cheema, S.K., Agellon, L.B. 2000. The murine and human cholesterol 7a-hydroxylase gene promoters are differentially responsive to regulation by fatty acids via peroxisome proliferator-activated receptor a. J. Biol. Chem. 275 12530-12536. 

CHARACTERIZATION OF A RESPONSE ELEMENT FOR PEROXISOMAL PROLIFERATOR ACTIVATED RECEPTOR (PPRE) IN HUMAN MUSCLE-TYPE CARNITINE PALMITOYLTRANSFERASE I... 

The abbreviations used are HMG-CoA, 3-hydroxy-3-melhylglutaryl-CoA CAT, chloramphenicol acetyltransferase PPAR, peroxisome proliferator-activated receptor PPRE, peroxisome proliferator-responsive element NRRE, nuclear receptor responsive element RXR, retinoid X receptor hRXRa, human 9-cis-retinoic acid receptor a mPPARa, mouse peroxisome proliferator-activated receptor a COUP-TP, chicken ovalbumin upstream-promoter transcription factor, HNF-4, hepatocyte nuclear factor 4 EMSA, electrophoretic mobility shift analysis tk, thymidine kinase NEFA, nonesterified fatty acids... 

Hsu, M. H., Savas, U., Griffin, K. J., and Johnson, E. F. (2001). Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proUferator-activated receptor alpha in HepG2 cells. J Biol Chem 276, 27950-27958. 

Hepatic peroxisome proliferation depends on a nuclear receptor, PPARa, to mediate these responses in mice, based on lack of response to peroxisome proliferators in PPARa-deficient mice. In one study with another peroxisome proliferator, WY-14,643, carcinogenesis was shown to be dependent on the same receptor. Oral administration of di(2-ethylhexyl) phthalate failed to elicit markers of peroxisome proliferation in PPARa-deficient mice, while the same treatment elicited this response in normal mice. Metabolites of di(2-ethylhexyl) phthalate caused activation of PPARa-mediated gene expression in mammalian cell co-transfection assays. Differences between responsive rodents and humans in various aspects of PPARa-mediated regulation of gene expression are consistent with the lack of activity of di(2-ethylhexyl) phthalate metabolites in hepatocyte cultures from 12 people studied to date. 

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