title: Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.
abstract: OBJECTIVE
  Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model.
  
  
  METHODS
  To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH.
  
  
  RESULTS
  Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies.
  
  
  CONCLUSIONS
  The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH.
authors.affiliation: Department of Endoscopy and Ultrasound, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Seki
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takaya
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Shimozato
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Furukawa
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Saikawa
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Asada
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
keywords: hepatic fibrogenesis; hepatocarcinogenesis; losartan; non-alcoholic steatohepatitis; sitagliptin