Pharmacological characterization of a human-specific peroxisome proliferater-activated receptor α (PPARα) agonist in dogs

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a key regulator in lipid metabolism and a potential therapeutic target for lipid-related metabolic diseases. It has been shown that there are species differences between human and mouse in response to several PPARα agonists in a transactivation assay. In the present study, we cloned a full length of dog PPARα and investigated the effects of a novel and potent agonist (KCL) for human PPARα. In a transactivation assay using the full length of PPARα, agonistic activity of KCL for dog PPARα (EC 50: 0.007 μM) was comparable to that for human PPARα (EC 50: 0.003 μM), but not that for rat PPARα (EC 50: 11.49 μM). Similar results were obtained from a transactivation assay using a GAL4/PPARα ligand-binding domain (LBD) chimera. A point-mutation study showed that I272 on PPARαLBD is a major contributor to species differences in response to KCL between human, dog, and rat PPARα. KCL also induced mRNA levels of HMG-CoA synthase in dog hepatocytes. When administered orally to dogs and rats, KCL significantly decreased plasma triglyceride levels in a dose-dependent manner. The triglyceride-lowering effects of KCL in dogs were >100-fold more potent than those in rats. These results suggest that KCL may induce activation of highly potent PPARα in humans as well as dogs, and that dog is a suitable animal model for studying and predicting the biological actions of potent agonists for human PPARα.