Abstract 19434: The Novel PPARalpha-Selective Agonist K-877 Improves Dyslipidemia, Enhances Reverse Cholesterol Transport and Decreases Inflammation and Atherosclerosis
Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing HDL functionality and reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated transcription factor, controls plasma lipid metabolism, macrophage cholesterol handling as well as the inflammatory response.
Objective: To study whether pharmacological activation of PPARalpha with the highly potent PPARalpha ligand, K-877, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in human apoA-I transgenic mice and in the human apolipoprotein E2 knock-in mouse (apo E2KI) model of mixed dyslipidemia and atherosclerosis.
Methods and results: In polarized Caco-2/TC7 human intestinal epithelium cells, K-877 treatment decreased apoB secretion and increased the expression of PPARalpha target genes involved in fatty acid oxidation and intestinal HDL production. Moreover, K-877 induced secretion of apoA-I in HDL particles. In primary human macrophages, K-877 promoted macrophage cholesterol efflux to HDL. K-877 treatment of human apoA-I transgenic mice induced plasma HDL cholesterol and apoA-I levels. Moreover, K-877 stimulated in vivo RCT in these mice. In addition, K-877 treatment exerted anti-inflammatory properties in murine and human macrophages. K-877 treatment not only improved the lipid profile, but also reduced inflammatory and macrophage marker gene expression in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apo E2KI mice.
Conclusion: These results demonstrate that the novel PPARalpha agonist K-877 exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
- © 2013 by American Heart Association, Inc.