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Journal of Gastroenterology
Published in: Journal of Gastroenterology 3/2014

01-03-2014 | Original Article—Liver, Pancreas, and Biliary Tract

Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats

Authors: Kosuke Kaji, Hitoshi Yoshiji, Yasuhide Ikenaka, Ryuichi Noguchi, Yosuke Aihara, Akitoshi Douhara, Kei Moriya, Hideto Kawaratani, Yusaku Shirai, Junichi Yoshii, Koji Yanase, Mitsuteru Kitade, Tadashi Namisaki, Hiroshi Fukui

Published in: Journal of Gastroenterology | Issue 3/2014

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Abstract

Background

Dipeptidyl peptidase-4 inhibitor (DPP4-I) is clinically used as a new oral antidiabetic agent. Although DPP4 is reportedly associated with the progression of chronic liver diseases, the effect of DPP4-I on liver fibrosis development is still obscure. This study was designed to elucidate the effect of DPP4-I on liver fibrosis development in conjunction with the activated hepatic stellate cells (Ac-HSCs).

Methods

The antifibrotic effect of DPP4-I was assessed in vivo and in vitro using porcine serum-induced experimental liver fibrosis model. DPP4-I, sitagliptin, at a clinically comparable low dose was administered by gavage daily.

Results

DPP4-I significantly attenuated liver fibrosis development along with the suppression of hepatic transforming growth factor (TGF)-β1, total collagen, and tissue inhibitor of metalloproteinases-1 in a dose-dependent manner. These suppressive effects occurred almost concurrently with the attenuation of HSCs activation. Our in vitro studies showed that DPP4-I inhibited platelet-derived growth factor-BB-mediated proliferation of the Ac-HSCs as well as upregulation of TGF-β1 and α1(I)-procollagen at magnitudes similar to those of the in vivo studies. The inhibitory effects of DPP4-I against HSCs proliferation and fibrogenic gene expression are mediated through the inhibition of the phosphorylation of ERK1/2, p38 and Smad2/3, respectively.

Conclusions

DPP4-I markedly inhibits liver fibrosis development in rats via suppression of HSCs proliferation and collagen synthesis. These suppressive effects are associated with dephosphorylation of ERK1/2, p38 and Smad2/3 in the HSCs. Since DPP4-I is widely used in clinical practice, this drug may represent a potential new therapeutic strategy against liver fibrosis in the near future.
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Metadata
Title
Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats
Authors
Kosuke Kaji
Hitoshi Yoshiji
Yasuhide Ikenaka
Ryuichi Noguchi
Yosuke Aihara
Akitoshi Douhara
Kei Moriya
Hideto Kawaratani
Yusaku Shirai
Junichi Yoshii
Koji Yanase
Mitsuteru Kitade
Tadashi Namisaki
Hiroshi Fukui
Publication date
01-03-2014
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 3/2014
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-013-0783-4

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