Dendrobium officinale polysaccharide ameliorate hyperlipidemia through LKB1/AMPK and CD36/PGC-1α/UCP1 activation and...

Dendrobium officinale polysaccharide (DOP) is recognized for its potential therapeutic effects on hyperlipidemia; however, its specific mechanisms in modulating lipid metabolism within hepatic and adipose tissues, along with its influence on the gut microbiota, have yet to be fully elucidated. Our study identified that the monosaccharide constituents of DOP comprise mannose, glucose, rhamnose, galactose, xylose, and arabinose. Network pharmacology analysis further indicated that the AMPK signaling pathway serves as a principal target of DOP. Using SD rats (8 weeks old, weighing 220-250 g), a hyperlipidemia model was established through a high-sugar, high-fat diet. Administration of DOP for 45 days resulted in significant reductions in total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), accompanied by an elevation in high-density lipoprotein cholesterol (HDL-C). Histopathological evaluation revealed an improvement in hepatic steatosis. At the molecular level within hepatic tissue, DOP treatment restored the expression of liver kinase B1 (LKB1) and the AMP-activated protein kinase (AMPK), while concurrently suppressing HMG-CoA reductase (HMGCR), sterol regulatory element-binding protein 1 (SREBF1), and phosphorylated acetyl-CoA carboxylase 1 (ACC1). In adipose tissue, DOP downregulated the cluster of differentiation 36 (CD36) expression and upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and uncoupling protein 1 (UCP1). Gut microbiota analysis demonstrated an increased abundance of Bacteroidota, Verrucomicrobiota, and Akkermansiaceae, alongside a decrease in Firmicutes and Actinobacteriota. Correlation analyses revealed that genera were correlated with serum lipid levels. Collectively, these findings suggest that DOP mitigates hyperlipidemia through modulation of the hepatic LKB1/AMPK signaling pathway and its downstream targets HMGCR, SREBF1, and ACC1, activation of the adipose CD36/PGC-1α/UCP1 pathway, and restoration of gut microbiota homeostasis, indicating a close relationship with the gut-liver axis.