Peroxisome proliferator-activated receptor PPAR pathway

More than 70% of differentiated thyroid cancer concentrates radioiodine after TSH stimulation (Robbins et al., 1991 Jarzab et al., 2003). Some differentiated thyroid cancer (approximately 10-20%), as well as anaplastic thyroid cancer, however, do not concentrate radioiodide, even after TSH stimulation (Robbins et al., 1991). Since almost all differentiated thyroid cancer expresses TSHR (Brabant et al, 1991), the absence of NIS induction in response to TSH is most likely due to defects in postreceptor signaling pathways. Recent studies have demonstrated the potential for NIS induction in poorly differentiated thyroid cancer by redifferentiation agents, such as nuclear receptor ligands, RA and peroxisome proliferator-activated receptor- (PPAR ) ligands, and inhibitors of epigenetic modifications. 

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.

It is too early to definitively identify the molecular mechanism(s) by which CLA, or specific isomers thereof, modulate immune reactivity and reduce disease. Peroxisomal proliferator-activated receptor-y (PPAR-y) activation has been proposed as a mechanism by which CLA exerts some of its biological effects (23). Although PPAR-y may play a role in some of the effects caused by dietary CLA, and these effects could be mediated via the downregulation of the NFkB pathway (24), there are some inconsistencies in the isomer-specific effects on the regulation of COX-2 and some of the products of the NFkB pathway. For example, Yu et al. (23) demonstrated that both the t9,cll and the tl0,cl2 isomers of CLA increase PPAR-y, and decrease TNFa however, only the c9,tll isomer decreased endotoxin-induced TNFa (12). If CLA-fed animals are more resistant to endotoxin (above) and if endotoxin downregulates PPAR-y (24), could PPAR-y regulation explain the wide array of effects attributed to dietary CLA ... 

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