As for the mechanism, our study suggests that the beneficial effects of Feno-FA on CNV are through PPARα activation, consistent with our previous study using a DR model.
19 A recent study, however, reported that fenofibrate inhibits CNV partially through cytochrome P450, a target independent of PPARα.
20 This disparity may be explained by the following reasons. (1) The study by Gong et al.
20 used fenofibrate, whereas we used Feno-FA. Fenofibrate, a third-generation fibric acid derivative, is a prodrug, which is hydrolyzed by tissue and plasma esterases to the active metabolite Feno-FA. Fenofibrate is >90% plasma bound, reaches peak concentration in the plasma at approximately 7 hours, and has an elimination half-life of approximately 20 hours.
41 Feno-FA contains a carboxylic acid moiety but not an isopropyl ester moiety in fenofibrate.
42 Feno-FA is a PPARα agonist, while fenofibrate is a LXR antagonist.
43 Fenofibrate may have some off-target effects. It was shown that fenofibrate is a potent inhibitor of cytochrome P450 with affinity >10 times higher than that of PPARα.
44 Li et al.
45 reported that fenofibrate inhibits voltage-dependent K
+ channel (Kv) expression in vascular smooth muscle, while neither another PPARα activator, bezafibrate, affects the Kv current, nor PPARα inhibitor GW6471 changes the inhibitory effect of fenofibrate, indicating that the effect of fenofibrate is independent of PPARα activation.
45 In addition, fenofibrate suppresses the growth of human hepatocellular carcinoma cells, which was not affected by the PPARα antagonist (GW6471) or by a PPARα-specific siRNA, also suggesting a PPARα-independent mechanism.
46 Fenofibrate affects retinal endothelial cell survival through the AMPK signal pathway in a PPARα independent manner as well.
47 (2) We used a lower dose (25 mg/kg/day) of the drug that is similar to the clinical dose in human patients, while Gong et al.
20 used fenofibrate at 100 mg/kg/day. Fenofibrate at high dose may confer off-target effects. The detailed mechanism for the different observations using
Pparα−/− mice remains to be elucidated.