Journal of gastroenterology, 2016-02, Vol.51 (2), p.162-172
2016
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- Autor(en) / Beteiligte
- Titel
- Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis
- Ist Teil von
- Journal of gastroenterology, 2016-02, Vol.51 (2), p.162-172
- Ort / Verlag
- Tokyo: Springer Japan
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Background and Aims Ursodeoxycholic acid (UDCA) is considered to be effective in the treatment of nonalcoholic steatohepatitis (NASH), particularly in combination with other pharmacological agents. UDCA reportedly counteracts the effects of endotoxemia. Previously, we demonstrated attenuated hepatic fibrogenesis and suppression of activated hepatic stellate cells (Ac-HSC) with an angiotensin-II (AT-II) type 1 receptor blocker (ARB). Here we evaluated the simultaneous effect of both agents on hepatic fibrogenesis in a rat model of NASH. Methods Fischer 344 rats were fed a choline-deficient l -amino-acid-defined (CDAA) diet for 8 weeks. The therapeutic effect of UDCA and ARB was evaluated along with hepatic fibrogenesis, lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. The direct inhibitory effect of both UDCA and ARB on Ac-HSC was assessed in vitro. Results Both UDCA and ARB had a potent inhibitory effect on hepatic fibrogenesis with suppression of the HSC activation and hepatic expression of transforming growth factor (TGF)-β1 and TLR4. UDCA decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption induced by the CDAA diet. ARB was found to directly suppress regulation of Ac-HSC. Conclusions UDCA and ARB have a synergistic repressive effect on hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing the activation of Ac-HSC. Because both agents are currently used in clinical practice, combined UDCA and ARB may represent a promising novel therapeutic approach for NASH.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0944-1174eISSN: 1435-5922DOI: 10.1007/s00535-015-1104-xTitel-ID: cdi_proquest_miscellaneous_1762968669
- Format
- –
- Schlagworte
- Abdominal Surgery, Actins - metabolism, Amino acids, Angiotensin, Angiotensin II Type 1 Receptor Blockers - therapeutic use, Animals, Biliary Tract, Cells, Cultured, Choline, Colorectal Surgery, Cytokines - metabolism, Drug Evaluation, Preclinical - methods, Drug Therapy, Combination, Endotoxins - metabolism, Gastroenterology, Health aspects, Hepatology, Inflammation Mediators - metabolism, Liver Cirrhosis - drug therapy, Liver Cirrhosis - etiology, Liver Cirrhosis - metabolism, Liver Cirrhosis - pathology, Male, Medicine, Medicine & Public Health, Non-alcoholic Fatty Liver Disease - complications, Non-alcoholic Fatty Liver Disease - drug therapy, Non-alcoholic Fatty Liver Disease - metabolism, Non-alcoholic Fatty Liver Disease - pathology, Original Article—Liver, Pancreas, Permeability, Rats, Inbred F344, Real-Time Polymerase Chain Reaction - methods, RNA, Messenger - genetics, Signal Transduction - drug effects, Surgical Oncology, Toll-Like Receptor 4 - biosynthesis, Toll-Like Receptor 4 - genetics, Transforming growth factors, Ursodeoxycholic Acid - therapeutic use, Ursodiol