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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3381

Title: Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.
Other Titles: ジペプチジルペプチターゼ4阻害剤(シタグリプチン)およびアンギオテンシンⅡ1型受容体遮断薬(ロサルタン)の併用療法は非糖尿病ラットモデルにおける非アルコール性脂肪肝炎の進行を抑制する
Authors: Okura, Yasushi
Namisaki, Tadashi
Moriya, Kei
Kitade, Mitsuteru
Takeda, Kosuke
Kaji, Kosuke
Noguchi, Ryuichi
Nishimura, Norihisa
Seki, Kenichiro
Kawaratani, Hideto
Takaya, Hiroaki
Sato, Shinya
Sawada, Yasuhiko
Shimozato, Naotaka
Furukawa, Masanori
Nakanishi, Keisuke
Saikawa, Soichiro
Kubo, Takuya
Asada, Kiyoshi
Yoshiji, Hitoshi
Keywords: hepatic fibrogenesis
non-alcoholic steatohepatitis
Issue Date: 28-Dec-2016
Publisher: John Wiley & Sons, Inc.
Citation: Hepatology research Vol.47 No.12 p.1317-1328 (2017 Nov)
Abstract: AIM: Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. METHODS: To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. RESULTS: Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. CONCLUSIONS: The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH.
Description: 博士(医学)・乙第1406号・平成29年9月27日
© 2016 The Japan Society of Hepatology
Copyright © 2016 John Wiley & Sons, Inc. All Rights Reserved.
This is the pre-peer reviewed version of the following article: Hepatology research [Epub ahead of print] (2016 Dec 28), which has been published in final form at http://dx.doi.org/10.1111/hepr.12860. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
URI: http://hdl.handle.net/10564/3381
ISSN: 13866346
Academic Degrees and number: 24601B1406
Degree-granting date: 2017-09-27
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2017年度

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