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Related Experiment Videos

Peroxisome proliferator-activated receptors: structures and function

J D Tugwood1, T C Aldridge, K G Lambe

  • 1Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.

Annals of the New York Academy of Sciences
|December 27, 1996
PubMed
Summary
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Human PPAR alpha exhibits significant variation, explaining why humans are less responsive to peroxisome proliferators compared to rodents. Genetic differences in PPAR alpha influence its function and expression, impacting response to these compounds.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Genetics

Background:

  • Peroxisome proliferators (PPs) exert pleiotropic effects, primarily mediated by PPAR alpha in rodents.
  • Humans appear unresponsive to PPs, a phenomenon not fully understood at the molecular level.
  • PPAR alpha (peroxisome proliferator-activated receptor alpha) is a key mediator of PP effects in responsive species.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind human unresponsiveness to PPs.
  • To investigate the role of human PPAR alpha (hPPAR alpha) structure and function in species-specific responses.
  • To explore interindividual variations in hPPAR alpha.

Main Methods:

  • Analysis of human PPAR alpha (hPPAR alpha) cDNAs from different individuals.

Related Experiment Videos

  • Sequencing and functional assessment of hPPAR alpha variants.
  • Quantification of hPPAR alpha transcript expression in human liver tissues.
  • Comparison of hPPAR alpha tissue-specific expression with rodent models.

    • Main Results:

    • Considerable variation in hPPAR alpha cDNAs, including structural changes (exon deletions) and single nucleotide polymorphisms leading to amino acid substitutions.
    • Identified a hPPAR alpha variant incapable of transcriptional activation by potent PPs.
    • Human liver hPPAR alpha transcript expression varies significantly between individuals (up to tenfold).
    • Human PPAR alpha exhibits a different tissue-specific expression profile compared to rodents, with generally lower levels in the liver.

    Conclusions:

    • Human and rodent PPAR alpha receptors differ significantly in molecular and biochemical characteristics.
    • Interindividual variation in hPPAR alpha structure and function exists within the human population.
    • Human genetic polymorphism in PPAR alpha may explain the apparent paradox of species-specific responses to peroxisome proliferators.