The inhibitory effect of Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on development of liver fibrosis in congenital diabetic fatty rats

Abstract

Since insulin resistance (IR) critically exacerbates liver fibrosis in chronic liver diseases, improvement of IR by anti-diabetic agents could serve as a novel therapy to prevent liver fibrosis. In the current study, we elucidated the effect of a sodium-glucose cotransporter-2 inhibitor (SGLT2-I) on liver fibrogenesis in terms of liver fibrosis rat models where porcine serum (PS) was injected intra-peritoneally to congenital diabetic OLETF rat or non-diabetic LETO rat. Different concentrations of ipragliflozin (3 mg/kg and 6 mg/kg) were orally administered during the experimental period. Serological and histological changes were examined at the end of experimental period. Direct effect of ipragliflozin on a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro. OLETF rats developed severe liver fibrosis by PS injection, but not LETO rats. Treatment with ipragliflozin markedly attenuated PS-mediated liver fibrosis and upregulate fibrotic markers along with improvement of IR in a dose-dependent manner in OLETF rats. Intriguingly, in vitro study showed that ipragliflozin affected neither cell proliferation nor fibrogenic activities in HSCs, suggesting that ipragliflozin can attenuate liver fibrogenesis, independent on improving IR. In conclusion, our dataset suggest that SGLT2-I might prevent liver fibrogenesis for NASH, independent of improvement of IR.