PPARa pathway

It is suggested that PPARa activation may lead to DNA replication, cell growth, and inhibition of apoptosis via tumor necrosis factor a (TNF-a). Alternatively or additionally, the oxidative stress could activate the MAP kinase pathway, which will also influence cell growth (Fig. 7.11), but this might be independent of PPARa activation. However, the role of these events is still unclear. 

The first relevance on pain was activation of PPARa in the spinal cord of rats with peripheral inflammation (Benani et al., 2004). Electrophoretic mobility-shift assay was employed to compare the DNA-binding activity toward a PPRE. The PPARa isoform was observed to be activated in the rat spinal cord after complete Freund s adjuvant injection, which could elicit hyperalgesia. PPARa was provided as a new player in the molecular modeling of pain pathways, although it was discussed that inhibitors of PPARa activation might be relevant antinociceptive drugs. 

Research demonstrated that CLA isomers reduce body fat in growing animals (29-31) and its actions on fat and energy metabolism may, in part, be directed through changes in both PPARa and PPARy (32, 33). In addition, specific effects of CLA isomers on activity and expression of enzymes associated with anabohc pathways of lipid metabolism are reported (34). Eor example, CLA was observed to decrease the mRNA level of the A9-desaturase enzyme in both liver tissue and hepatocyte cultures (35). 

This hepatomegaly is correlated to PPARa activation of acyl-CoA oxidase (AOX), the first enzyme of peroxisomal /3-oxidation of fatty acids and a gene with a PPRE in its promoter region14. In addition, hepatic mitochondrial /3-oxidation and microsomal w-oxidation of fatty acids are increased, as a direct result of PPARa activation of mRNA of specific enzymes associated with these pathways (carnitine palmitoyl transferase I and cytochrome P4504A, respectively). Activation of fatty acid oxidation by these three pathways would lead to enhanced fatty acid oxidation, given the appropriate substrate. PPARa has also been shown to enhance delivery of fatty acids to the oxidizing systems (Fig. 3). 

Other growth signaling pathways may be involved in PPARa activator growth responses, but overall the data supporting their role is usually confined to gene expression data. Due to the lack of useful genetic models, thrae is little mechanistic data, which shows causal links between specific pathways and modulation of cell fate except for the role of PPARa and NF-kB activation (discussed below). 

Recently, some studies have started to unravel how the PPARa signalling pathway functions (Fig. 1.4). In the absence of exogenously added ligand, PPARa resides in the nucleus where it exhibits high mobility (Feige et al.,... 

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