PPAR activation

Current evidence suggests that PPAR activation may limit inflammation and hence atherosclerosis. Both PPAR-a and PPAR-y can reduce T-cell activation, as shown by decreased production of EFN-y. PPAR-a agonists also rqness endothelial VCAM-1 expression and inhibit the inflammatory activation of vascular SMCs, while PPAR-y agonists repress endothelial chemokine expression and decrease macrophage MMP production. 

PPAR is a nuclear receptor-transcription factor and is ligand-dependent and expressed in several tissues. It is initially involved in adipocyte differentiation and fatty acid synthesis. Fatty acid and eicosanoids bind to PPAR and regulate transcription. PPAR activation inhibits monocyte differentiation and expression of several pro-inflammatory genes such as iNOS, TNF, etc. PPAR activation inhibits tumor cell proliferation (epithelial, colon, prostate). PPAR is involved in angiogenesis. 

Bums, K. A., and Vanden Heuvel, J. P. (2007). Modulation of PPAR activity via phosphoylation. Biochim Biophys Acta 1771, 952-960. 

Mukherjee, R., Jow, L., Noonan, D., and McDonnell, D. P. (1994). Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol 51, 157-166. 

Figure 8.4. A model of the transcriptional regulation of gene expression by PPARa. The PPARa binds as a heterodimer with RXR to PPREs upstream of target genes. Ligand binding to either the RXR or PPAR activates the transcriptional complex resulting in the induction of numerous genes involved in fatty acid oxidation and metabolism, such as CYP4A.

Buse JB, Rubin CJ, Frederich R, et al. Muraglitazar, a dual (a/y) PPAR activator a randomized, double-blind. 

Peroxisome ProUferator-Activated Receptor (PPAR) Activation... 

PPAR activator and after 48 h the cells were harvested and CAT activity was measured. 

As can be seen in Table I cotransfection of MCPT I-CAT and PPARs expression vectors led to a marked increase in CAT activity in the presence of the PPAR activators. Surprisingly, even though PPAR5 is able to bind the MCPT I PPRE in vitro it does not activate the expression of the chimeric gene even in the presence of linoleic acid as activator. 

Modulation of eicosanoids, increased apoptosis, reduced proliferation, and PPAR activation appear to be involved in the anticarcinogenic activity of CLA. Of particular interest are the recent data on the reduction of murine mammary tumor metas-... 

Molecular Field Analysis in the Design of Dual PPAR Activators. 168... 

Therefore, the MCFAs increase the energy expenditure, reduce the fat mass and prevent the development of insulin resistance through the PPARs activation (Figure 1). 

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