The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor α (PPARα) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARα. The guinea-pig PPARα showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P≈ 0.06). The guinea-pig PPARα cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARα RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARα mediated any physiological effects, guinea pigs were exposed to two selective PPARα agonists, Wy-14,643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.
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June 1998
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Research Article|
June 15 1998
Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia
Alex R. BELL;
Alex R. BELL
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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Richard SAVORY;
Richard SAVORY
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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Neill J. HORLEY;
Neill J. HORLEY
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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Agharul I. CHOUDHURY;
Agharul I. CHOUDHURY
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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Maurice DICKINS;
Maurice DICKINS
†GlaxoWellcome plc, Park Road, Ware, Herts. SG12 0DP, U.K.
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Tim J. B. GRAY;
Tim J. B. GRAY
‡Sanofi Research, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, U.K.
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Andrew M. SALTER;
Andrew M. SALTER
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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David R. BELL
David R. BELL
1
*School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
November 19 1997
Revision Received:
February 26 1998
Accepted:
March 17 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 332 (3): 689–693.
Article history
Received:
November 19 1997
Revision Received:
February 26 1998
Accepted:
March 17 1998
Citation
Alex R. BELL, Richard SAVORY, Neill J. HORLEY, Agharul I. CHOUDHURY, Maurice DICKINS, Tim J. B. GRAY, Andrew M. SALTER, David R. BELL; Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia. Biochem J 15 June 1998; 332 (3): 689–693. doi: https://doi.org/10.1042/bj3320689
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