並列タイトル等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
一般注記type:Thesis
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.
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.
identifier:Hepatology research Vol.47 No.12 p.1317-1328 (2017 Nov)
identifier:13866346
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3381
identifier:Hepatology research, 47(12): 1317-1328
DOIinfo:doi/10.1111/hepr.12860
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