Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis

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 Lamino-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)-beta 1 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.