PPAR response elements

TCACCT n TCACCT (PPRE PPAR Response Element)... 

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.

The major increase in the mRNA levels of fatty acyl-CoA oxidase did not appear until 8-12h after administration of TTA (Vaagenes H. et. al, Biochem. Pharmacol, in press). The gene for this enzyme contains a PPAR-responsive element. It is, therefore, interesting to speculate whether PPAR is responsible for mediating the effects of TTA on CPT-1 and/or CPT 11 which are induced earlier than fatty acyl-CoA oxidase. 

TTA induces peroxisomal and mitochondrial P-oxidation enzymes in addition to several other enzymes in lipid metabolism. Furthermore, TTA functions as a ligand for PPAR-a and PPAR-y and it stimulates both peroxisomal and mitochondrial proliferation. An increasing amount of genes that are known to carry PPAR response elements (PPREs) is reported, and differential regulation by these receptors is likely to affect the growth potential. The result of TTA treatment is a reorganization of the cellular lipid metabolism towards an increased metabolic activity. 

Both POVPC and PGPC can induce expression of monocyte chemotactic protein-1 (MCP-1) and IL-8 in ECs, which are well-known markers of inflammation. The signaling pathway responsible for both gene expressions was linked with activation of PPARa and transcription of genes of the PPAR response element. 

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