PMID- 31177586 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1386-6346 (Print) IS - 1386-6346 (Linking) VI - 49 IP - 10 DP - 2019 Oct TI - Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase-4 inhibitor on hepatic fibrosis. PG - 1147-1161 LID - 10.1111/hepr.13385 [doi] AB - 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)-beta1, alpha1(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-beta1 and alpha1(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. CI - (c) 2019 The Japan Society of Hepatology. FAU - Shimozato, Naotaka AU - Shimozato N AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Namisaki, Tadashi AU - Namisaki T AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kaji, Kosuke AU - Kaji K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kitade, Mitsuteru AU - Kitade M AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Okura, Yasushi AU - Okura Y AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Sato, Shinya AU - Sato S AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Moriya, Kei AU - Moriya K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Seki, Kenichiro AU - Seki K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kawaratani, Hideto AU - Kawaratani H AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Takaya, Hiroaki AU - Takaya H AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Sawada, Yasuhiko AU - Sawada Y AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Saikawa, Soichiro AU - Saikawa S AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Nakanishi, Keisuke AU - Nakanishi K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Furukawa, Masanori AU - Furukawa M AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Fujinaga, Yukihisa AU - Fujinaga Y AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kubo, Takuya AU - Kubo T AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Asada, Kiyoshi AU - Asada K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kitagawa, Koh AU - Kitagawa K AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Tsuji, Yuki AU - Tsuji Y AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Kaya, Daisuke AU - Kaya D AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Ozutsumi, Takahiro AU - Ozutsumi T AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Akahane, Takemi AU - Akahane T AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Mitoro, Akira AU - Mitoro A AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. FAU - Yoshiji, Hitoshi AU - Yoshiji H AD - Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan. LA - eng PT - Journal Article DEP - 20190715 PL - Netherlands TA - Hepatol Res JT - Hepatology research : the official journal of the Japan Society of Hepatology JID - 9711801 OTO - NOTNLM OT - hepatic stellate cell OT - non-alcoholic steatohepatitis OT - obeticholic acid OT - sitagliptin EDAT- 2019/06/10 06:00 MHDA- 2019/06/10 06:01 CRDT- 2019/06/10 06:00 PHST- 2018/12/28 00:00 [received] PHST- 2019/05/18 00:00 [revised] PHST- 2019/05/22 00:00 [accepted] PHST- 2019/06/10 06:00 [pubmed] PHST- 2019/06/10 06:01 [medline] PHST- 2019/06/10 06:00 [entrez] AID - 10.1111/hepr.13385 [doi] PST - ppublish SO - Hepatol Res. 2019 Oct;49(10):1147-1161. doi: 10.1111/hepr.13385. Epub 2019 Jul 15.