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

Journal of Gastroenterology Aims and scope Submit manuscript

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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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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Correspondence to Hitoshi Yoshiji.

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Kaji, K., Yoshiji, H., Ikenaka, Y. et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol 49, 481–491 (2014). https://doi.org/10.1007/s00535-013-0783-4

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  • DOI: https://doi.org/10.1007/s00535-013-0783-4

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