H. Keller et al., PPAR-ALPHA STRUCTURE-FUNCTION-RELATIONSHIPS DERIVED FROM SPECIES-SPECIFIC DIFFERENCES IN RESPONSIVENESS TO HYPOLIPIDEMIC AGENTS, Biological chemistry, 378(7), 1997, pp. 651-655
The nuclear receptor PPAR alpha is a key regulatory transcription fact
or in lipid homeostasis, some liver detoxification processes and the c
ontrol of inflammation. Recent findings suggest that many hypolipidemi
c drugs and anti-inflammatory agents can potentially act by binding to
PPAR alpha and inducing its activity, Here, we identify some structur
e-function relationships in PPAR alpha, by using the species-specific
responsiveness to the two hypolipidemic agents, Wy 14,643 and 5,8,11,1
4-eicosatetraynoic acid (ETYA). We first show that the species-specifi
c differences are mediated primarily via the ligand binding domain of
the receptor and that these two drugs are indeed ligands of PPAR alpha
. By mutagenesis analyses we identify amino acid residues in the ligan
d binding domains of Xenopus, mouse and human PPAR alpha, that confer
preferential responsiveness to ETYA and Wy 14,643. These findings will
aid in the development of new synthetic PPAR alpha ligands as effecti
ve therapeutics for lipid-related diseases and inflammatory disorders.