A Hypothetical Mechanism for Fat-Induced Rodent Hepatocarcinogenesis

  • Daniel J. Noonan
  • Michelle L. O’Brien
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 422)


The regulation of fat metabolism in higher eukaryotes appears to be intimately associated with the activities of a family of recently identified nuclear receptors called ‘peroxisome proliferator-activated receptors’ (PPAR). In 1990, Issemann and Green1 reported the cloning of a mouse steroid receptor superfamily member that they characterized as a peroxisome proliferator-responsive transcription factor. The steroid receptor family of genes consists of a group of ligand-activated DNA transcription factors that bind regulatory sequences upstream of their target gene(s) resulting in the activation or repression of specific gene transcription.2–4 Subsequently it has been shown that PPAR is a small family of genes with reports of at least α, β and γ isoforms in mouse,5,6 Xenopus,7 rat8 and humans.9,10 An examination of PPAR regulatable promoters suggest this receptor family is intimately involved in fat metabolism including their breakdown,11,12 storage13 and synthesis.14 The complexity of the PPAR activation pathway has been substantially enhanced by the demonstration that PPAR DNA binding is linked to heterodimerization with a member of the retinoid X (RXR) family of receptors,15 and more recent PPAR transcription studies in yeast where it was demonstrated that PPAR activity is contingent upon both RXR and perhaps other mammalian cell-specific factor(s).16 The RXR family of receptors appear to be a point of convergence for several members of the intracellular receptor superfamily of genes17–19 and play a critical role in the transcriptional events associated with these receptors. All of the data accumulated to date clearly implicate PPAR-regulated events in the homeostasis of fats and suggest they may serve as viable targets for drug intervention and regulation of fat metabolism.


Phytanic Acid Juvenile Hormone Clofibric Acid Liver Fatty Acid Binding Protein Hypothetical Mechanism 
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Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Daniel J. Noonan
    • 1
    • 2
  • Michelle L. O’Brien
    • 2
  1. 1.Department of BiochemistryUniversity of KentuckyLexingtonUSA
  2. 2.Graduate Center for ToxicologyUniversity of KentuckyLexingtonUSA

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