Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats

Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient L-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH. Treatment with both LOS and DSX suppressed choline-deficient L-amino acid-defined diet-induced liver fibrosis development and hepatocarcinogenesis. This combination treatment exerted a stronger inhibitory effect compared with treatment with a single agent. These inhibitory effects occurred almost concurrently with the suppression of oxidative stress, neovascularization, and HSC activation. Our in vitro study demonstrated that LOS and DSX inhibited angiotensin II-induced proliferation, transforming growth factor-beta(1) expression of activated HSC, and in vitro angiogenesis. These results indicated that dual inhibition by combined treatment of LOS and DSX attenuated the progression of NASH. Since both agents are widely used in clinical practice, this combination therapy may represent a potential new strategy against NASH in the near future.