A Novel Insulin Sensitizer Acts as a Coligand for Peroxisome Proliferator-Activated Receptor-α (PPAR-α) and PPAR-γ Effect of PPAR-αActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats

摘要

We investigated the biological activity of a novel thia- zolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike BRL-49,653, restored reduced lipid oxidation, that is, CO_2 and ketone body production from [~14C]palmitic acid, in the liver by 39/100 (P<0.05) and 57/200 (P<0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we exam- ined the effect on peroxisome proiferator-activated receptor 9PPAR) isoforms, which may play key roles in lipid metabolism.