Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats
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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).
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.
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.
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.
KeywordsDPP4 Liver fibrosis Hepatic stellate cells TGF-β Collagen
Activated hepatic stellate cells
Chronic hepatitis C
Dipeptidyl peptidase-4 inhibitor
Extracellular-signal regulated kinase 1/2
Fibroblast activation protein
Glucagon-like peptide 1
c-Jun N-terminal kinase
Mitogen-activated protein kinase
Tetrazolium 3-(4, 5-dimethylthiazol-2,5-yl)-2,5-diphenyltetrazolium bromide
Primary biliary cirrhosis
Platelet-derived growth factor
α-Smooth muscle actin
Transforming growth factor-β1
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