Effective Combination Therapy of Angiotensin-II Receptor Blocker and Rifaximin for Hepatic Fibrosis in Rat Model of Nonalcoholic Steatohepatitis

• Published in: International journal of molecular sciences Vol. 21; no. 15; p. 5589
• Main Authors: Fujinaga, Yukihisa, Kawaratani, Hideto, Kaya, Daisuke, Tsuji, Yuki, Ozutsumi, Takahiro, Furukawa, Masanori, Kitagawa, Koh, Sato, Shinya, Nishimura, Norihisa, Sawada, Yasuhiko, Takaya, Hiroaki, Kaji, Kosuke, Shimozato, Naotaka, Moriya, Kei, Namisaki, Tadashi, Akahane, Takemi, Mitoro, Akira, Yoshiji, Hitoshi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.08.2020; MDPI
• Subjects: Angiotensin; Angiotensin II; Angiotensin Receptor Antagonists - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensins - genetics; Animals; ARB; Cell activation; Choline; Combination therapy; Disease Models, Animal; Encephalopathy; Endotoxins; Epithelial cells; Fibrosis; Gene expression; Growth factors; Hepatic encephalopathy; hepatic fibrosis; Hepatic Stellate Cells - drug effects; Humans; Insulin; Insulin resistance; Intestine; Lipopolysaccharides; Lipopolysaccharides - toxicity; Liver; Liver - drug effects; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Metabolic syndrome; Microbiota; NASH; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - pathology; Oxidation resistance; Oxidative stress; Oxidative Stress - drug effects; Permeability; Rats; rifaximin; Rifaximin - pharmacology; Signal Transduction - drug effects; Stellate cells; TLR4 protein; Toll-like receptors; Transforming growth factor-b; Vascular endothelial growth factor; Zonula occludens-1 protein; metabolic syndrome; ARB; NASH; hepatic fibrosis; rifaximin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21155589

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-β 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.