Stevioside alleviates high-fat diet-induced MASLD/MASH in Apo-E‑/‑ mice by modulating the TGF-β signaling.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health issue characterized by excessive hepatic fat accumulation, which can progress to inflammation and fibrosis. This condition is closely linked to systemic metabolic disorders, including obesity, type 2 diabetes, and dyslipidemia. Due to the absence of approved pharmacological treatments, identifying effective therapeutic strategies is essential. Stevioside (STV), a natural sweetener with documented bioactive properties, was evaluated for its potential to alleviate MASLD in both in vitro and in vivo models. In vitro, STV dose-dependently suppressed transforming growth factor-beta (TGF-β)-induced fibrogenic activation in hepatic stellate cells (HSC-LX2). In the in vivo model, MASLD was induced in ApoE-deficient (ApoE⁻/⁻) mice by feeding a high-fat diet (HFD) for 10 weeks, resulting in an average body weight of approximately 45 g. Further, mice were randomized and assigned to chow control, HFD control, or STV treatment groups for another 6-week intervention. STV administration significantly attenuated HFD-induced weight gain, dyslipidemia, and liver injury markers. Histological analyses revealed substantial reductions in hepatic steatosis, inflammation, and fibrosis in STV-treated mice. Mechanistic investigations (in in vitro and in vivo models) indicated that STV mitigates disease progression by modulating the canonical TGF-β/Smad signaling pathway. Overall, these findings demonstrate that STV effectively alleviates MASLD in ApoE⁻/⁻ mice and inhibits fibrogenic activation in HSC-LX2 cells, highlighting its potential as a therapeutic agent for MASLD.