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01 奈良県立医科大学 >
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0122 学位請求論文 >
01221 博士論文(医学) >
2019年度 >
このアイテムの引用には次の識別子を使用してください:
http://hdl.handle.net/10564/3728
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タイトル: | Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis. |
その他のタイトル: | 肝線維化に対するファルネソイドX受容体アゴニストとジペプチジルペプチダーゼ-4阻害薬の併用効果 |
著者: | Shimozato, Naotaka![](/dspace/image/metalink/link_ja.gif) Namisaki, Tadashi![](/dspace/image/metalink/link_ja.gif) Kaji, Kosuke Kitade, Mitsuteru Okura, Yasushi Sato, Shinya Moriya, Kei![](/dspace/image/metalink/link_ja.gif) Seki, Kenichiro Kawaratani, Hideto![](/dspace/image/metalink/link_ja.gif) Takaya, Hiroaki![](/dspace/image/metalink/link_ja.gif) Sawada, Yasuhiko![](/dspace/image/metalink/link_ja.gif) Saikawa, Soichiro![](/dspace/image/metalink/link_ja.gif) Nakanishi, Keisuke Furukawa, Masanori Fujinaga, Yukihisa Kubo, Takuya Asada, Kiyoshi Kitagawa, Koh Tsuji, Yuki Kaya, Daisuke Ozutsumi, Takahiro Akahane, Takemi![](/dspace/image/metalink/link_ja.gif) Mitoro, Akira![](/dspace/image/metalink/link_ja.gif) Yoshiji, Hitoshi![](/dspace/image/metalink/link_ja.gif) |
キーワード: | hepatic stellate cell non-alcoholic steatohepatitis obeticholic acid sitagliptin |
発行日: | 2019年10月 |
出版者: | Wiley / The Japan Society of Hepatology |
引用: | Hepatology research Vol.49 No.10 p.1147-1161 (2019 Oct) |
抄録: | Aim: Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. Methods: Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro. Results: Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC. Conclusions: Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH. |
内容記述: | 博士(医学)・甲第737号・令和2年3月16日 © 2019 The Japan Society of Hepatology This is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1111/hepr.13385], which has been published in final form at [https://doi.org/10.1111/hepr.13385]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
URI: | http://hdl.handle.net/10564/3728 |
ISSN: | 13866346 |
DOI: | https://doi.org/10.1111/hepr.13385 |
学位授与番号: | 24601A737 |
学位授与年月日: | 2020-03-16 |
学位名: | 博士(医学) |
学位授与機関: | 奈良県立医科大学 |
出現コレクション: | 2019年度
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