PPARa Ligands

Structure activity studies in vitro have revealed that the relative potency of peroxisome proliferators seems to be determined by a combination of lipophilicity and the calculated binding affinity to the mouse PPARa ligand-binding domain. 

PPARa ligands do not induce cell proliferation or suppress apoptosis in human hepatocytes in vitro (Goll et al. 1999 Hasmall et al. 1999 Perrone et al. 1998 Williams and Perrone 1996). Many of these studies included a positive control to ensure that human hepatocytes were of sufficient quality to mount a positive growth response. In comparison, rat or mouse primary hepatocytes exposed to PPARa activators exhibit up to 8-fold induction in cell proliferation (summarized in (Klaunig et al. 2003)). There are no data on human hepatocyte proliferation in vivo, although in vivo and in vitro data from nonhuman primates show cell proliferation is not induced by PPARa activators [Table 17.3 and reviewed in Doull et al. (1999)]. In summary, available data suggest that PPARa activators are unlikely to alter apoptosis and proliferation in human hepatocytes. 

The PPARa ligands, named peroxisome proliferators (PPs) include a wide range of structurally diverse molecules which induce, primarily in rodent... 

PUFAs are naturally occurring PPARa ligands, which are hypothesized to activate fatty acid oxidation. Although n-6 PUFAs can activate PPARa, n-3 PUFAs are more potent PPARa activators in vivo (reviewed by Schmitz and Ecker, 2008). Among n-3 PUFAs, EPA is the strongest PPARa activator while ALA and DHA are weak activators but can be converted in vivo into EPA (Jump, 2008). Interestingly, eicosanoids are even stronger activators of PPARa than EPA (reviewed by Schmitz and Ecker, 2008). 

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