PMID- 32759852 OWN - NLM STAT- MEDLINE DCOM- 20210217 LR - 20210217 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 21 IP - 15 DP - 2020 Aug 4 TI - Effective Combination Therapy of Angiotensin-II Receptor Blocker and Rifaximin for Hepatic Fibrosis in Rat Model of Nonalcoholic Steatohepatitis. LID - 10.3390/ijms21155589 [doi] LID - 5589 AB - The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-beta and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis. FAU - Fujinaga, Yukihisa AU - Fujinaga Y AUID- ORCID: 0000-0003-2402-574X AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Kawaratani, Hideto AU - Kawaratani H AUID- ORCID: 0000-0002-4361-0592 AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Kaya, Daisuke AU - Kaya D AUID- ORCID: 0000-0003-2922-5679 AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Tsuji, Yuki AU - Tsuji Y AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Ozutsumi, Takahiro AU - Ozutsumi T AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Furukawa, Masanori AU - Furukawa M AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Kitagawa, Koh AU - Kitagawa K AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Sato, Shinya AU - Sato S AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Nishimura, Norihisa AU - Nishimura N AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Sawada, Yasuhiko AU - Sawada Y AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Takaya, Hiroaki AU - Takaya H AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Kaji, Kosuke AU - Kaji K AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Shimozato, Naotaka AU - Shimozato N AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Moriya, Kei AU - Moriya K AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Namisaki, Tadashi AU - Namisaki T AUID- ORCID: 0000-0002-3158-5318 AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Akahane, Takemi AU - Akahane T AUID- ORCID: 0000-0002-6675-0475 AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Mitoro, Akira AU - Mitoro A AUID- ORCID: 0000-0002-6666-5633 AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. FAU - Yoshiji, Hitoshi AU - Yoshiji H AD - Department of Gastroenterology, Nara Medical University, Nara 634-8522, Japan. LA - eng PT - Journal Article DEP - 20200804 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Angiotensins) RN - 0 (Lipopolysaccharides) RN - L36O5T016N (Rifaximin) SB - IM MH - Angiotensin Receptor Antagonists/*pharmacology MH - Angiotensin-Converting Enzyme Inhibitors/pharmacology MH - Angiotensins/genetics MH - Animals MH - Disease Models, Animal MH - Hepatic Stellate Cells/drug effects MH - Humans MH - Lipopolysaccharides/toxicity MH - Liver/drug effects/pathology MH - Liver Cirrhosis/chemically induced/*drug therapy/genetics/pathology MH - Non-alcoholic Fatty Liver Disease/chemically induced/*drug therapy/genetics/pathology MH - Oxidative Stress/drug effects MH - Rats MH - Rifaximin/*pharmacology MH - Signal Transduction/drug effects PMC - PMC7432739 OTO - NOTNLM OT - ARB OT - NASH OT - hepatic fibrosis OT - metabolic syndrome OT - rifaximin COIS- The authors declare no conflict of interest. EDAT- 2020/08/08 06:00 MHDA- 2021/02/18 06:00 PMCR- 2020/08/01 CRDT- 2020/08/08 06:00 PHST- 2020/07/23 00:00 [received] PHST- 2020/07/29 00:00 [revised] PHST- 2020/08/02 00:00 [accepted] PHST- 2020/08/08 06:00 [entrez] PHST- 2020/08/08 06:00 [pubmed] PHST- 2021/02/18 06:00 [medline] PHST- 2020/08/01 00:00 [pmc-release] AID - ijms21155589 [pii] AID - ijms-21-05589 [pii] AID - 10.3390/ijms21155589 [doi] PST - epublish SO - Int J Mol Sci. 2020 Aug 4;21(15):5589. doi: 10.3390/ijms21155589.