Article: article from journal or magazin.
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Peroxisome proliferator-activated receptors: finding the orphan a home.
Molecular and Cellular Endocrinology
Publication types: Journal Article ; Review
Publication Status: ppublish
Publication Status: ppublish
The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about ten fold in the livers of treated rodents. Additional peroxisome proliferator responsive genes include other peroxisomal beta-oxidation enzymes and members of the cytochrome P450 IVA family. A peroxisome proliferator response element (PPRE), consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has been identified in the upstream regulatory sequences of each of these genes. The retinoid X receptor (RXR) forms a heterodimer with PPAR and binds to the PPRE. Furthermore, the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. Interestingly, a variety of fatty acids can activate PPAR supporting the suggestion that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR and that the physiological role of PPAR is to regulate fatty acid homeostasis. Taken together, the discovery of PPAR has opened up new opportunities in understanding how lipid homeostasis is regulated, how the fibrate hypolipidaemic drugs may act and should lead to improvements in the assessment of human risk from peroxisome proliferators based upon a better understanding of their mechanism of action.
Acyl-CoA Oxidase, Animals, Antilipemic Agents/pharmacology, Antilipemic Agents/toxicity, Base Sequence, Carcinogens/pharmacology, Carcinogens/toxicity, Clofibrate/pharmacology, Clofibrate/toxicity, Cytochrome P-450 Enzyme System/genetics, Cytochrome P-450 Enzyme System/metabolism, Fatty Acids/metabolism, Fatty Acids/pharmacology, Liver Neoplasms, Experimental/chemically induced, Mice, Microbodies/drug effects, Microbodies/enzymology, Molecular Sequence Data, Multigene Family, Oxidation-Reduction, Oxidoreductases/genetics, Oxidoreductases/metabolism, Pyrimidines/pharmacology, Pyrimidines/toxicity, Rats, Receptors, Cytoplasmic and Nuclear/classification, Receptors, Cytoplasmic and Nuclear/drug effects, Receptors, Steroid/classification, Receptors, Steroid/genetics, Recombinant Fusion Proteins/metabolism, Repetitive Sequences, Nucleic Acid, Steroids/pharmacology, Transcription Factors/classification, Transcription Factors/drug effects
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