title: Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice.
abstract: OBJECTIVE
  Dipeptidyl peptidase-4 inhibitors are used for treatment of patients with type 2 diabetes. In addition to glycemic control, these agents showed beneficial effects on lipid metabolism in clinical trials. However, the mechanism underlying the lipid-lowering effect of dipeptidyl peptidase-4 inhibitors remains unclear. Here, we investigated the lipid-lowering efficacy of anagliptin in a hyperlipidemic animal model, and examined the mechanism of action.
  
  
  METHODS
  Male low-density lipoprotein receptor-deficient mice were administered 0.3% anagliptin in their diet. Plasma lipid levels were assayed and lipoprotein profile was analyzed using high-performance liquid chromatography. Hepatic gene expression was examined by deoxyribonucleic acid microarray and quantitative polymerase chain reaction analyses. Sterol regulatory element-binding protein transactivation assay was carried out in vitro.
  
  
  RESULTS
  Anagliptin treatment significantly decreased the plasma total cholesterol (14% reduction, P < 0.01) and triglyceride levels (27% reduction, P < 0.01). Both low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol were also decreased significantly by anagliptin treatment. Sterol regulatory element-binding protein-2 messenger ribonucleic acid expression level was significantly decreased at night in anagliptin-treated mice (15% reduction, P < 0.05). Anagliptin significantly suppressed sterol regulatory element-binding protein activity in HepG2 cells (21% decrease, P < 0.001).
  
  
  CONCLUSIONS
  The results presented here showed that the dipeptidyl peptidase-4 inhibitor, anagliptin, exhibited a lipid-lowering effect in a hyperlipidemic animal model, and suggested that the downregulation of hepatic lipid synthesis was involved in the effect. Anagliptin might have beneficial effects on lipid metabolism in addition to a glucose-lowering effect.
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yano
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Ito
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Itou
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Yasumura
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshinaka
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Sumihiko
authors.initials: S
authors.lastname: Hagita
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co, Ltd, Mie, Japan.
authors.forename: Moritaka
authors.initials: M
authors.lastname: Goto
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Tokyo New Drug Research Laboratories, Kowa Company, Ltd, Tokyo, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Tanabe
authors.affiliation: Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D008074:Lipoproteins / Q000096:biosynthesis / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008074:Lipoproteins; D011743:Pyrimidines; D012333:RNA, Messenger; D011973:Receptors, LDL; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D002784:Cholesterol; C583175:anagliptin
keywords: Anagliptin; Dipeptidyl peptidase-4 inhibitor; Lipid metabolism