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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3890

Title: TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats.
Other Titles: TGR5活性化はアナグリプチンによる糖尿病ラットに対する肝線維化抑制効果を増強する
Authors: Kaya, Daisuke
Kaji, Kosuke
Tsuji, Yuki
Yamashita, Satoko
Kitagawa, Koh
Ozutsumi, Takahiro
Fujinaga, Yukihisa
Takaya, Hiroaki
Kawaratani, Hideto
Moriya, Kei
Namisaki, Tadashi
Akahane, Takemi
Yoshiji, Hitoshi
Keywords: dipeptidyl peptidase-4 inhibitors
hepatic stellate cells
oleanolic acid
Takeda G protein-coupled receptor 5
Issue Date: 26-Sep-2019
Publisher: MDPI
Citation: Cells Vol.8 No.10 Article No.1153 (2019 Sep)
Abstract: Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.
Description: 博士(医学)・甲第766号・令和3年3月15日
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
URI: http://hdl.handle.net/10564/3890
ISSN: 20734409
DOI: https://doi.org/10.3390/cells8101153
Academic Degrees and number: 24601A766
Degree-granting date: 2021-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2020年度

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