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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3728

Title: Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis.
Other Titles: 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
Authors: Shimozato, Naotaka
Namisaki, Tadashi
Kaji, Kosuke
Kitade, Mitsuteru
Okura, Yasushi
Sato, Shinya
Moriya, Kei
Seki, Kenichiro
Kawaratani, Hideto
Takaya, Hiroaki
Sawada, Yasuhiko
Saikawa, Soichiro
Nakanishi, Keisuke
Furukawa, Masanori
Fujinaga, Yukihisa
Kubo, Takuya
Asada, Kiyoshi
Kitagawa, Koh
Tsuji, Yuki
Kaya, Daisuke
Ozutsumi, Takahiro
Akahane, Takemi
Mitoro, Akira
Yoshiji, Hitoshi
Keywords: hepatic stellate cell
non-alcoholic steatohepatitis
obeticholic acid
sitagliptin
Issue Date: Oct-2019
Publisher: Wiley / The Japan Society of Hepatology
Citation: Hepatology research Vol.49 No.10 p.1147-1161 (2019 Oct)
Abstract: 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.
Description: 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
Academic Degrees and number: 24601A737
Degree-granting date: 2020-03-16
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2019年度

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