Dendrobine's mechanism: alleviating cholesterol metabolism disorders via FXR/LXR modulation in NAFLD mouse livers

Cholesterol homeostasis is tightly regulated through hepatic synthesis, intestinal absorption, and biliary excretion, with bile acids serving as critical regulators of cholesterol catabolism. Dysregulated cholesterol metabolism and bile acid imbalance are hallmarks of non-alcoholic fatty liver disease (NAFLD), contributing to hepatic lipid accumulation and disease progression. Dendrobine (DNE), a bioactive alkaloid from Dendrobium nobile, has emerged as a potential therapeutic candidate for lipid metabolic disorders.

C57BL/6J mice were fed a high-fat diet to establish an NAFLD model, followed by DNE administration. Hepatic steatosis and cholesterol deposition were evaluated via histology and biochemical assays; bile acid profiles were quantified by LC-MS/MS. Gene and protein expression were analyzed using RT-qPCR and Western blotting. In vitro studies using cholesterol-laden HepG2 cells further explored DNE's mechanisms, validated by specific pharmacological agonists and inhibitors of the Farnesoid X receptor (FXR) and liver X receptor (LXR) pathways.

DNE significantly ameliorated hepatic steatosis and reduced cholesterol accumulation in HFD-induced NAFLD mice. LC-MS/MS analysis revealed that DNE substantially expanded the bile acid (BA) pool in the liver, bile, and ileum. Mechanistically, DNE comprehensively modulated cholesterol absorption, biotransformation, and transport by modulating the FXR and LXR signaling pathways. It robustly upregulated key genes involved in BA synthesis (e.g., Cyp7a1) and efflux, while downregulating transporters responsible for BA and cholesterol reuptake (e.g., Ntcp, Npc1l1). In vitro validation using specific pharmacological agonists and antagonists further confirmed that DNE upregulates CYP7A1 and promotes BA synthesis via a dual FXR/LXRα-dependent regulatory network.

Our findings suggest that DNE modulates cholesterol homeostasis and alleviates NAFLD in conjunction with BA synthesis, transport, and absorption, in a manner associated with the FXR/LXRα regulatory network, presenting a promising therapeutic strategy.