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

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. © 2017 the authors