Journal of Gastroenterology

, Volume 49, Issue 3, pp 481–491

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

  • 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
Original Article—Liver, Pancreas, and Biliary Tract

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.

Keywords

DPP4 Liver fibrosis Hepatic stellate cells TGF-β Collagen 

Abbreviations

Ac-HSCs

Activated hepatic stellate cells

CHC

Chronic hepatitis C

DM

Diabetes mellitus

DPP4-I

Dipeptidyl peptidase-4 inhibitor

ECM

Extracellular matrix

ERK1/2

Extracellular-signal regulated kinase 1/2

FAP

Fibroblast activation protein

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

GLP-1

Glucagon-like peptide 1

HCC

Hepatocellular carcinoma

JNK

c-Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

MTT

Tetrazolium 3-(4, 5-dimethylthiazol-2,5-yl)-2,5-diphenyltetrazolium bromide

NASH

Nonalcoholic steatohepatitis

PBC

Primary biliary cirrhosis

PDGF

Platelet-derived growth factor

α-SMA

α-Smooth muscle actin

TGF-β1

Transforming growth factor-β1

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Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Kosuke Kaji
    • 1
  • Hitoshi Yoshiji
    • 1
  • Yasuhide Ikenaka
    • 1
  • Ryuichi Noguchi
    • 1
  • Yosuke Aihara
    • 1
  • Akitoshi Douhara
    • 1
  • Kei Moriya
    • 1
  • Hideto Kawaratani
    • 1
  • Yusaku Shirai
    • 1
  • Junichi Yoshii
    • 1
  • Koji Yanase
    • 1
  • Mitsuteru Kitade
    • 1
  • Tadashi Namisaki
    • 1
  • Hiroshi Fukui
    • 1
  1. 1.Third Department of Internal MedicineNara Medical UniversityKashiharaJapan

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