Ganoderic Acid A Alleviates High‐Fat Diet‐Induced Lipid Metabolism Disorders in Mice by Inhibiting Intestinal Farnesoid X Receptor

ABSTRACT Lipid metabolism disorders (LMDs) can cause many metabolic diseases and seriously threaten human health. It is necessary to develop safe drugs for long‐term use in LMDs patients. Ganoderma lucidum ( G. lucidum ), as an edible and traditional medicinal mushroom, has been widely used for its health benefits in Asian countries. Ganoderic acid A (GA), an important bioactive product from G. lucidum , has multiple pharmacological activities. Farnesoid X receptor (FXR) is a ligand‐activated nuclear receptor involved in regulate lipid absorption and metabolism. Recently, FXR has emerged as a promising therapeutic target for LMD. The purpose of this study was to determine whether GA can alleviate LMDs and to elucidate its mechanism in a high‐fat diet‐induced LMD mouse model. GA administration attenuated the weight gain, hyperlipidemia, and hepatic lipid accumulation in LMD model mice. Metabolomic analysis revealed that GA inhibited intestinal lipid absorption. The intestinal expressions of FXR target genes, including Ibabp , Fgf15 , and Shp , was significantly decreased by GA (20 mg/kg), indicating that GA inhibits intestinal FXR activity. Oral lipid tolerance test disclosed that the inhibitory effect of GA on intestinal FXR significantly reduced lipid absorption. Surface plasmon resonance and thermal drift experiments revealed that GA bound FXR and competitively inhibited its activity. These data suggest that GA reduces lipid accumulation and hyperlipemia by inhibiting intestinal FXR.