title: Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association.
abstract: BACKGROUND
  Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels.
  
  
  METHODS
  Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay.
  
  
  RESULTS
  The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23%, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 μM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220%, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 μM) decreased basal CETP mRNA levels by 21%, and this was completely reversed by T0901317.
  
  
  CONCLUSIONS
  Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis.
  
  
  BACKGROUND
  UMIN Clinical Trials Registry ID UMIN000019020.
authors.affiliation: Department of Clinical Laboratory and Nephrology, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Clinical Laboratory and Nephrology, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan. hkimura@u-fukui.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Internal Medicine, Fukui Chuo Clinic, 4-5-10, Matsumoto, Fukui, 910-0003, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Oida
authors.affiliation: Division of Endocrinology, Fukui-ken Saiseikai Hospital, 7-1, Funahashi, Wadanaka, 918-8503, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kanehara
authors.affiliation: Division of Endocrinology, Fukui-ken Saiseikai Hospital, 7-1, Funahashi, Wadanaka, 918-8503, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Bando
authors.affiliation: Division of Internal Medicine, Yasukawa Hospital, 2-108, Owada, Fukui, 910-0005, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakamoto
authors.affiliation: Division of Endocrinology, Fukui Prefectural Hospital, 2-8-1, Yotsui, Fukui, 910-8526, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Wakasugi
authors.affiliation: Division of Internal Medicine, Tanaka Hospital, 2-3-1 Ohte, Fukui, Fukui, 910-0005, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saga
authors.affiliation: Research and Development Department, Denka Seiken Co. Ltd, Tokyo, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kamiyama
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mikami
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwano
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Nephrology, Department of Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.|Division of Nephrology, Obama Municipal Hospital, 2-2 Ohte, Obama, Fukui, 917-8567, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000368:Aged; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood* / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy; D000071518:Liver X Receptors / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology; D016896:Treatment Outcome; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D006845:Hydrocarbons, Fluorinated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D011804:Quinolines; D013449:Sulfonamides; C506642:CETP protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C108475:pitavastatin
keywords: CETP; Liver X receptor; Pitavastatin; Small dense LDL-C; T0901317