Macrostemonoside I alleviates metabolic dysfunction-associated steatotic liver disease in mice: potential involvement of SCAP/SREBP2 signaling in cholesterol metabolism

IntroductionThe progression of metabolic dysfunction-associated steatotic liver disease (MASLD) involves lipotoxicity and inflammation from disordered cholesterol metabolism. Macrostemonoside I (MI), an Allium saponin monomer, may regulate cholesterol metabolism, but its role in MASLD is unclear.MethodsMASLD was induced in mice by a 6-week choline-deficient high-fat diet (CDAHFD) (1-week gradual transition to CDAHFD and 5 weeks of continuous CDAHFD feeding), followed by treatment with MI (2, 4, 8 mg/kg/d), atorvastatin, or vehicle for 30 days. Body weight, liver index, serum levels of HDL-C, ALT, AST and inflammatory cytokines were measured. Hepatic cholesterol content, histopathology (H&E, Oil Red O, Sirius red, Immunofluorescent staining), oxidative stress markers, transcriptome and the expression of genes/proteins related to cholesterol metabolism and fibrosis were analyzed.ResultsMI reduced liver index, ameliorated hepatic ballooning and steatosis, and decreased hepatic total cholesterol and free cholesterol, as well as serum ALT/AST levels, but had no significant effect on HDL-C. It reduced hepatic CD11b⁺ infiltration and serum IL-1β, IL-6, TNF-α levels. Liver fibrosis area, and the fibrosis markers COL1A1 and α-SMA, were downregulated. MI also decreased hepatic ROS and MDA, and increased SOD activity. Furthermore, MI treatment was associated with changes in the cholesterol transcriptome and with significant reductions in both the mRNA and protein levels of the cholesterol metabolism-related molecules SCAP and SREBP2.DiscussionMI might alleviate MASLD by reducing cholesterol accumulation, suppressing inflammation, ameliorating fibrosis, and mitigating oxidative stress, potentially via SCAP/SREBP2 pathway. However, causality remains to be determined.