title: Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.
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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Shirai
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000068900:Sitagliptin Phosphate; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011719:Pyrazines; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D000077214:Becaplermin; D003094:Collagen; D000068900:Sitagliptin Phosphate