Lupeol improves bile acid metabolism and metabolic dysfunction-associated steatotic liver disease in mice via FXR signaling pathway and gut-liver axis

Metabolic dysfunction-associated steatotic liver disease (MASLD) has a multifactorial and complex pathogenesis. Notably, the disorder of Bile acid (BA) metabolism and lipid metabolism-induced lipotoxicity are the main risk factors of MASLD. Lupeol, traditional regional medicine from Xinjiang, has a long history of use for its anti-inflammatory, anti-tumor, and immune-modulating properties. Recent research suggests its potential as a therapeutic option for MASLD due to its proposed binding capacity to the nuclear BA receptor, Farnesoid X receptor (FXR), hence could represent a therapeutic option for MASLD. In this study, a natural triterpenoid drug lupeol improved BA metabolism and MASLD in mice through the FXR signaling pathway and the gut-liver axis. Furthermore, lupeol effectively restored gut healthiness and improved intestinal immunity, barrier integrity, and inflammation, as indicated by the reconstructed gut flora. Compared with fenofibrate (Feno), lupeol treatment significantly reduced weight gain, fat deposition, and liver injury, decreased serum total cholesterol (TC) and triglyceride (TG) levels, and alleviated hepatic steatosis and liver inflammation. BA analysis showed that lupeol treatment accelerated BA efflux and decreased uptake of BA by increasing hepatic FXR and bile salt export pump (BSEP) expression. Gut microbiota alterations could be related to enhanced fecal BA excretion in lupeol-treated mice. Therefore, consumption of lupeol may prevent HFD-induced MASLD and BA accumulation, possibly via the FXR signaling pathway and regulating the gut microbiota. • The BA receptor FXR is a ligand-activated nuclear protein on the nucleus of cells, whose activation is the key to the BA-dependent mechanism of inhibiting lipid metabolism for the treatment of MASLD. However, whether lupeol can act as an FXR agonist in MASLD remains unclear. • FFA-induced HepG2 cells were used to investigate the inhibitory effect of lupeol on lipid droplet generation. The ability of lupeol to inhibit lipid droplet generation in vitro and to exist as an FXR agonist was determined using si-FXR. • In animal studies, lupeol treatment effectively modulated intestinal flora and improved intestinal permeability. • Lupeol regulated HFD-induced MASLD and BA metabolism through FXR signaling pathway and enterohepatic axis. • Lupeol may act as an FXR agonist and activate FXR signaling to prevent and treat HFD-induced MASLD.