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Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice

AIMS/INTRODUCTION: 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 pept...

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Autores principales: Yano, Wataru, Inoue, Noriyuki, Ito, Shiori, Itou, Takahiro, Yasumura, Misako, Yoshinaka, Yasunobu, Hagita, Sumihiko, Goto, Moritaka, Nakagawa, Takashi, Inoue, Keisuke, Tanabe, Sohei, Kaku, Kohei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334308/
https://www.ncbi.nlm.nih.gov/pubmed/27860391
http://dx.doi.org/10.1111/jdi.12593
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author Yano, Wataru
Inoue, Noriyuki
Ito, Shiori
Itou, Takahiro
Yasumura, Misako
Yoshinaka, Yasunobu
Hagita, Sumihiko
Goto, Moritaka
Nakagawa, Takashi
Inoue, Keisuke
Tanabe, Sohei
Kaku, Kohei
author_facet Yano, Wataru
Inoue, Noriyuki
Ito, Shiori
Itou, Takahiro
Yasumura, Misako
Yoshinaka, Yasunobu
Hagita, Sumihiko
Goto, Moritaka
Nakagawa, Takashi
Inoue, Keisuke
Tanabe, Sohei
Kaku, Kohei
author_sort Yano, Wataru
collection PubMed
description AIMS/INTRODUCTION: 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. MATERIALS AND 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.
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spelling pubmed-53343082017-03-06 Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice Yano, Wataru Inoue, Noriyuki Ito, Shiori Itou, Takahiro Yasumura, Misako Yoshinaka, Yasunobu Hagita, Sumihiko Goto, Moritaka Nakagawa, Takashi Inoue, Keisuke Tanabe, Sohei Kaku, Kohei J Diabetes Investig Articles AIMS/INTRODUCTION: 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. MATERIALS AND 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. John Wiley and Sons Inc. 2016-12-15 2017-03 /pmc/articles/PMC5334308/ /pubmed/27860391 http://dx.doi.org/10.1111/jdi.12593 Text en © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Articles
Yano, Wataru
Inoue, Noriyuki
Ito, Shiori
Itou, Takahiro
Yasumura, Misako
Yoshinaka, Yasunobu
Hagita, Sumihiko
Goto, Moritaka
Nakagawa, Takashi
Inoue, Keisuke
Tanabe, Sohei
Kaku, Kohei
Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title_full Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title_fullStr Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title_full_unstemmed Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title_short Mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
title_sort mechanism of lipid‐lowering action of the dipeptidyl peptidase‐4 inhibitor, anagliptin, in low‐density lipoprotein receptor‐deficient mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334308/
https://www.ncbi.nlm.nih.gov/pubmed/27860391
http://dx.doi.org/10.1111/jdi.12593
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