Improvement of dyslipidemia, insulin sensitivity, and energy balance by a peroxisome proliferator–activated receptor α agonist

Abstract Peroxisome proliferator–activated receptor α (PPAR α ) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPAR α agonist that activated both human and rat PPAR α receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid β -oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPAR α -mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPAR α transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPAR α agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.