title: 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.
abstract: 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.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Takei
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan. Electronic address: ynakagawa@md.tsukuba.ac.jp.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Yunong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Song-Iee
authors.initials: SI
authors.lastname: Han
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Satoh
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan. Electronic address: hshimano@md.tsukuba.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D001583:Benzoxazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D055786:Gene Knockout Techniques; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D001583:Benzoxazoles; D002087:Butyrates; D005227:Fatty Acids; C000603947:K-877 compound; D047493:PPAR alpha; D011973:Receptors, LDL; D002784:Cholesterol
keywords: Cholesterol absorption; HDL cholesterol; PPARα; SPPARMα