Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis

Naotaka Shimozato; Tadashi Namisaki; Kosuke Kaji; Mitsuteru Kitade; Yasushi Okura; Shinya Sato; Kei Moriya; Kenichiro Seki; Hideto Kawaratani; Hiroaki Takaya; Yasuhiko Sawada; Soichiro Saikawa; Keisuke Nakanishi; Masanori Furukawa; Yukihisa Fujinaga; Takuya Kubo; Kiyoshi Asada; Koh Kitagawa; Yuki Tsuji; Daisuke Kaya; Takahiro Ozutsumi; Takemi Akahane; Akira Mitoro; Hitoshi Yoshiji

doi:10.1111/hepr.13385

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis

Hepatol Res. 2019 Oct;49(10):1147-1161. doi: 10.1111/hepr.13385. Epub 2019 Jul 15.

Authors

Naotaka Shimozato¹, Tadashi Namisaki¹, Kosuke Kaji¹, Mitsuteru Kitade¹, Yasushi Okura¹, Shinya Sato¹, Kei Moriya¹, Kenichiro Seki¹, Hideto Kawaratani¹, Hiroaki Takaya¹, Yasuhiko Sawada¹, Soichiro Saikawa¹, Keisuke Nakanishi¹, Masanori Furukawa¹, Yukihisa Fujinaga¹, Takuya Kubo¹, Kiyoshi Asada¹, Koh Kitagawa¹, Yuki Tsuji¹, Daisuke Kaya¹, Takahiro Ozutsumi¹, Takemi Akahane¹, Akira Mitoro¹, Hitoshi Yoshiji¹

Affiliation

¹ Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.

PMID: 31177586
DOI: 10.1111/hepr.13385

Abstract

Aim: Non-alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase-4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH.

Methods: Fifty Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac-HSCs) were assessed in vitro.

Results: Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac-HSC proliferation and hepatic transforming growth factor (TGF)-β1, α1(I)-procollagen, and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase-2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet-induced zonula occludens-1 disruption, whereas sitagliptin directly inhibited Ac-HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF-β1 and α1(I)-procollagen mRNA expression and p38 phosphorylation in Ac-HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac-HSC.

Conclusions: Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac-HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.

Keywords: hepatic stellate cell; non-alcoholic steatohepatitis; obeticholic acid; sitagliptin.