Peroxisome proliferator-activated receptors PPARs , fatty acid ligands

CLA has also been shown to be a good ligand of nuclear receptors called peroxisome proliferator activated receptors (PPAR) (45). CLA is specifically active on two PPAR isoforms, a and y. The isoform a is found mainly in liver and functions as a transcription factor for many enzymes involved in fatty acid oxidation and particularly, peroxisomal 3-oxidation. We recently detected peroxisomal 3-oxidation products of CLA and metabolites in rat tissues and in humans (unpublished data). This finding would prompt the question whether CLA, as a good substrate for peroxisomal 3-oxidation, has any effect on peroxisomal P-oxidation. Indeed, it has been reported that induction of several key enzymes of peroxisomal P-oxidation was through the activation of PPARa by CLA (45). 

Formation of CD 16-carbon fatty acids probably takes place in the peroxisomes which are known to shorten fatty acids and to release them outside of peroxisomes (4). Peroxisome metabolism is supported by the fact that CLA is a high-affinity ligand for peroxisome proliferator-activated receptors (PPAR), a family of transcription factors known to affect gene expression and glucose and lipid metabolism. In this chapter we will briefly review initial evidence of CLA isomer metabolism in peroxisomes and its possible implications for CLA biological activities. 

Both EPA and C14-S-acetic acid are converted to their respective CoA esters in mitochondria. Furthermore, in contrast to DHA-CoA, EPA-CoA and C14-S-acetyl-CoA are easily transferred into the mitochondria by the CAT system. EPA is more difficult to oxidize than saturated and monounsaturated fatty acids, due to the double bonds and C14-S-acetic acid is non-oxidizable by P-oxidation,due to the sulfur atom in 3-position. Thus, accumulation of their respective CoA esters in the mitochondria might give an fatty acid overload signal leading to inaeased mitochondrial fatty acid oxidation. C14-S-acetic acid mimics the effects of peroxisome proliferators such as the fibrates and it was recently shown that it may be a ligand for the peroxisome proliferating activated receptor (PPAR) a. As administration of the 3-thia fatty acids seem to force EPA to the mitochondria, an additional fish oil effect might be seen. 

Fig. 12. Panel A Inhibitory effects of various polyunsaturated fatty acids (PUFA) on sterol regulatory element binding protein (SREBP)-lc promoter activity. EtOH, ethanol SA, saturated fatty acid OL, oleic acid LA, linoleic acid DHA, docosa-hexaenoic acid EPA, eicosapentaenoic acid AA, arachidonic acid. Panel B Mechanism by which polyunsaturated fatty acids suppress the SREBP-1 c promoter activity, through an effect on the liver X receptor (LXR)/9-c/s-retinoic acid receptor (RXR) activation pathway [redrawn from Yoshikawa etal. (129), reproduced with permission]. PUFA competitively interfere with binding of the endogenous ligand (possibly oxysterols) to LXR, thereby repressing LXR/RXR transactivity and SREBP-lc and lipogenic gene expression. Meanwhile, PUFA can bind and activate peroxisome proliferator activated receptor-a (PPARa) to induce 3-oxidation of fatty acids. PPRE PPAR response element LXRE LXR response element.

---