PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents.

Details

Serval ID
serval:BIB_AC4D362C36DC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents.
Journal
Biological Chemistry
Author(s)
Keller H., Devchand P.R., Perroud M., Wahli W.
ISSN
1431-6730[print], 1431-6730[linking]
Publication state
Published
Issued date
07/1997
Volume
378
Number
7
Pages
651-655
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The nuclear receptor PPAR alpha is a key regulatory transcription factor in lipid homeostasis, some liver detoxification processes and the control of inflammation. Recent findings suggest that many hypolipidemic drugs and anti-inflammatory agents can potentially act by binding to PPAR alpha and inducing its activity. Here, we identify some structure-function relationships in PPAR alpha, by using the species-specific responsiveness to the two hypolipidemic agents, Wy 14,643 and 5,8,11,14-eicosatetraynoic acid (ETYA). We first show that the species-specific 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 ligand 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 effective therapeutics for lipid-related diseases and inflammatory disorders.
Keywords
5,8,11,14-Eicosatetraynoic Acid/pharmacology, Amino Acid Sequence, Animals, Antilipemic Agents/pharmacology, Humans, Mice, Microbodies/chemistry, Microbodies/drug effects, Molecular Sequence Data, Pyrimidines/pharmacology, Receptors, Cytoplasmic and Nuclear/chemistry, Receptors, Cytoplasmic and Nuclear/drug effects, Sequence Homology, Amino Acid, Species Specificity, Structure-Activity Relationship, Transcription Factors/chemistry, Transcription Factors/drug effects, Xenopus
Pubmed
Web of science
Create date
24/01/2008 16:05
Last modification date
20/08/2019 15:16
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