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PMID: 7539101 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.

Molecular and cellular biology ·Vol. 15 ·No. 6 ·1995-06-00 ·Pages 3012-22

Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ

Abstract

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.

MeSH Terms
Animals Base Sequence Clofibrate/pharmacology DNA, Complementary Liver/physiology,ultrastructure Mice Mice, Inbred C57BL Mice, Knockout Microbodies/drug effects,physiology,ultrastructure Microscopy, Electron Molecular Sequence Data Pyrimidines/pharmacology RNA/analysis Receptors, Cytoplasmic and Nuclear/deficiency,genetics Transcription Factors/deficiency,genetics
Chemicals
DNA, Complementary Pyrimidines Receptors, Cytoplasmic and Nuclear Transcription Factors RNA pirinixic acid Clofibrate
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Lee S S
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Pineau T
Drago J
Lee E J
Owens J W
Kroetz D L
Fernandez-Salguero P M
Westphal H
Gonzalez F J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.15.6.3012
Published
1995-06-00
Pages
3012-22
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC230532
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.15.6.3012 PMC Full Text View journal details
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