title: A selective peroxisome proliferator-activated receptor δ agonist PYPEP suppresses atherosclerosis in association with improvement of the serum lipoprotein profiles in human apolipoprotein B100 and cholesteryl ester transfer protein double transgenic mice.
abstract: OBJECTIVE
  Although peroxisome proliferator-activated receptor (PPAR) δ agonists have been shown to improve the serum lipoprotein profiles in humans, the impact of the changes in these lipoprotein profiles on atherosclerosis remains to be elucidated. The aim of this study was to investigate the relationship between the selective PPARδ agonist-induced alterations of serum lipoprotein profiles and the development of atherosclerosis in human apolipoprotein B100 and cholesterol ester transfer protein double transgenic (hApoB100/hCETP-dTg) mice with human-like hypercholesterolemic dyslipidemia.
  
  
  METHODS
  hApoB100/hCETP-dTg mice fed an atherogenic diet received a novel PPARδ agonist (PYPEP) or vehicle for 18 weeks, followed by evaluation of atherosclerosis. Serum samples were collected during the treatment period at least at 3-week intervals to determine the lipoprotein levels and the levels of an inflammatory marker, macrophage chemotactic protein-1 (MCP-1), and to analyze the lipoprotein profile by fast protein liquid chromatography. The cholesterol efflux capacity of high-density lipoprotein (HDL) was examined using [(3)H]-cholesterol labeled macrophages.
  
  
  RESULTS
  Compared with vehicle treatment, PYPEP treatment caused increases in the serum levels of HDL cholesterol and apolipoprotein A-I (ApoA-I), as well as reductions in the serum non-HDL cholesterol and MCP-1 levels. The HDL fraction from the PYPEP-treated group maintained its cholesterol efflux capacity and showed an increased population of smaller HDL particles. PYPEP substantially suppressed atherosclerotic lesion progression, and the lesion areas had significant correlations with non-HDL cholesterol, HDL cholesterol, ApoA-I and MCP-1 by Pearson's correlation analysis. A multiple regression analysis revealed that non-HDL cholesterol and ApoA-I were significantly associated with the atherosclerotic lesion area.
  
  
  CONCLUSIONS
  A novel PPARδ agonist, PYPEP, suppressed atherosclerotic lesion progression by improving the serum lipoprotein profiles, including increased levels of ApoA-I and functional HDL particles, as well as a reduced non-HDL cholesterol level, in hApoB100/hCETP-dTg mice with human-like hypercholesterolemic dyslipidemia.
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: noriyuki.naya@shionogi.co.jp.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Naya
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fukao
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Tadateru
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Uwabe
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Imagawa
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Nomura
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Seijiro
authors.initials: S
authors.lastname: Hara
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shinosaki
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Hanasaki
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D053299:Apolipoprotein B-100 / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D047494:PPAR delta / Q000819:agonists*; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; C506642:CETP protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D047494:PPAR delta; D010880:Piperidines; D011759:Pyrrolidines; C000607341:tert-butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)piperidine-1-carboxylate
keywords: Apolipoprotein A-I (ApoA-I); Atherosclerosis; High-density lipoprotein (HDL); Hypercholesterolemic dyslipidemia; Peroxisome proliferator-activated receptor (PPAR) δ agonist