Pharmacological characterization of a human-specific peroxisome proliferater-activated receptor alpha (PPARalpha) agonist in dogs.
Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha agonists in a transactivation assay. In the present study, we cloned a full length of dog PPARalpha and investigated the effects of a novel and potent agonist (KCL) for human PPARalpha. In a transactivation assay using the full length of PPARalpha, agonistic activity of KCL for dog PPARalpha (EC(50): 0.007 microM) was comparable to that for human PPARalpha (EC(50): 0.003 microM), but not that for rat PPARalpha (EC(50): 11.49 microM). Similar results were obtained from a transactivation assay using a GAL4/PPARalpha ligand-binding domain (LBD) chimera. A point-mutation study showed that I272 on PPARalphaLBD is a major contributor to species differences in response to KCL between human, dog, and rat PPARalpha. 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 PPARalpha 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 PPARalpha.
Nagasawa
Michiaki
M
Discovery Research Laboratories, Kyorin Pharmaceutical Co Ltd, 2399-1 Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Ide
Tomohiro
T
Suzuki
Masahiro
M
Tsunoda
Masaki
M
Akasaka
Yunike
Y
Okazaki
Takashi
T
Mochizuki
Toshiro
T
Murakami
Koji
K
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000032:analysis; D004285:Dogs; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D018076:DNA, Complementary; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011189:Potassium Chloride