Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice

• Published in: Journal of pharmacological sciences 2017-04, Vol.133 (4), p.214-222
• Main Authors: Takei, Kenta, Nakagawa, Yoshimi, Wang, Yunong, Han, Song-iee, Satoh, Aoi, Sekiya, Motohiro, Matsuzaka, Takashi, Shimano, Hitoshi
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - metabolism; Benzoxazoles - pharmacology; Benzoxazoles - therapeutic use; Butyrates - pharmacology; Butyrates - therapeutic use; Cholesterol - metabolism; Cholesterol absorption; Disease Models, Animal; Fatty Acids - metabolism; Gene Expression - drug effects; Gene Knockout Techniques; HDL cholesterol; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; Intestinal Absorption - drug effects; Intestine, Small - metabolism; Lipid Metabolism - drug effects; Liver - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Oxidation-Reduction - drug effects; PPAR alpha - agonists; PPAR alpha - genetics; PPARα; Receptors, LDL - genetics; SPPARMα
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2017.02.003

Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr−/−) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr−/− mice. K-877 administration to Ldlr−/− mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr−/− mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.