ABSTRACT
An Orphan Receptor Engages an Activator and Gets a Name: Activation of a Nuclear Receptor by PPs PPAR Finds a Place in Physiology: PPAR Activation by Physiologically Occurring Fatty Acids, Fatty-Acid Derivatives, and Eicosanoids Finding a Partner for PPAR and Target Genes for the Heterodimer: PPAR and the Retinoid X Receptor Act as a Heterodimer To Activate Genes Involved in Lipid Storage and Metabolism PPAR Finds Its Relatives: PPARs Compose a Family of Similar Proteins, but Activators/Ligands as well as Target Genes are Distinct PPARs from the Toxicologist’s Point of View: PPARs in Regulation of Cell Differentiation, Proliferation, and Cancer Guilty or Not? The Difficulties in Estimating Human Risks from Rodent and In-Vitro Studies Conclusions and Future Perspectives Acknowledgments References
Peroxisomes are relatively recently discovered cell organelles coated by a single membrane layer. Large numbers of peroxisomes are found in the liver but also in virtually all other eukaryotic cells including yeast [reviewed in (1)]. Peroxisomes contain structural proteins and enzymes that are encoded by nuclear genes and are imported into preexisting organelles (2). Peroxisomes contain a complete fatty acid ^-oxidation system in addition to that present in the mitochondria, and they carry enzymes involved in reactive oxygen metabolism such as rich supplies of catalase. The
jS-oxidation in peroxisomes is essential for very long-chain fatty acids and bile acids, which are poor substrates for the mitochondrial /3-oxidation system (3). Therefore, inheritable defects in peroxisome structure or function lead to severe degenerative diseases with the most prominent manifestation in the central nervous system, such as X-linked adrenoleukodystrophy or Zellweger syndrome [reviewed in (4)]. Deposits of very long-chain fatty acids in neuronal tissues due to a defect in metabolism appear to play an essential role in pathogenesis (3). /3-Oxidation by peroxisomes, in contrast to that by mitochondria, generates H20 2 during the acyl-coenzymeA (CoA) oxidation reaction that is degraded by rich supplies of catalase in the peroxisomes (1,5), but it may also give rise to other diffusable reactive oxygen species, DNA damage, and possibly cancer (6,7).
