Abstract 12867: The Mechanism of K-877, a Highly Potent and Selective Pparalpha Modulator, on Regulation of Synthesis, Secretion and Metabolism of Triglycerides and Cholesterol
Introduction: Triglycerides (TG) are one of the important risk factors for cardiovascular diseases. TG are synthesized via fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), and hydrolyzed by lipoprotein lipase (LPL). ApoC-III and angiopoietin-like 3 (angptl3) inhibit LPL activity. K-877 is a novel selective peroxisome proliferator-activated receptor (PPAR)α modulator for which Phase IIb/III trials have been completed in Japan. K-877 has demonstrated superior reduction of plasma TG. The mechanisms of regulation of synthesis, secretion and metabolism of TG on experimental animals are investigated in this study.
Methods: PPAR-selectivity was assessed using a reporter gene assay for PPARα, PPARγ and PPARδ. K-877 was administered to Zucker fatty (ZF) rats or normal SD rats. Lipid de novo synthesis and VLDL secretion from liver were monitored using radioisotope [14C] and the Triton-method. Plasma lipids, Angptl3, apoCIII, and LPL activity were measured. TG clearance in blood was assayed by injection of a soybean-oil suspension (Intralipid®). Gene expression in liver was evaluated by qRT-PCR.
Results: In cell-based reporter gene assays, K-877 showed high activity (EC50=0.08nM for PPARα) and subtype-selectivity (>5000, >11,000-fold for PPARγ, PPARδ, respectively). In ZF rats, a severe hypertriglyceridemia model, K-877 also reduced plasma TG significantly but fenofibrate reduced it slightly. In liver extirpated from ZF rats, K-877 reduced de novo synthesis of TG (72% inhibition) and cholesterol (Cho), as well as gene expression of FAS, ACC and DGAT2. The gene expression of ACO, CPT1 and FGF21 were increased by K-877. In SD rats, K-877 reduced plasma TG at 0.1-1mg/kg and Cho at 0.3-1mg/kg, respectively. K-877 decreased VLDL-TG and VLDL-Cho secretion from liver, and plasma Angptl3 and ApoCIII levels, and potentiated LPL activity in epididymal adipose tissue. An intralipid clearance test confirmed significant acceleration of TG clearance by K-877.
Conclusions: These results suggest that K-877 modulates lipid level by inhibiting TG and Cho synthesis, inhibiting VLDL secretion, accelerating TG clearance via LPL activation and increasing beta-oxidation. These mechanisms support the results in the clinical trials.
- © 2013 by American Heart Association, Inc.