Nuciferine activates intestinal TAS2R46 to attenuate metabolic disorders and hyperlipidemia via hepatic VLDL regulation

Abstract

Background

Dysregulated blood lipid metabolism, a primary driver of hyperlipidemia, is closely associated with excessive very low-density lipoprotein (VLDL) synthesis and secretion. Nuciferine, a bioactive compound isolated from lotus leaves, demonstrates remarkable hypolipidemic efficacy; however, its limited bioavailability challenges existing mechanistic explanations for this pronounced therapeutic effect.

Purpose

This research aims to investigate the disease-modifying effect and underlying mechanism of nuciferine against hyperlipidemia from a novel perspective by modulating the synthesis and secretion of VLDL.

Methods

High-fat diet-induced hyperlipidemic rats were assessed by biochemical assays and histopathological examinations to assess the therapeutic effect of nuciferine. Untargeted metabo-lipidomics were launched to obtain the metabolic and lipid profiles, and explainable machine learning algorithms were innovatively utilized in screening differentially expressed metabolites for pathway analysis. A hyperlipidemic two-layer cell co-culture model was analyzed using quantitative polymerase chain reaction, molecular docking, immunofluorescence, cellular thermal shift assay, western blotting, and flow cytometry to delineate VLDL regulatory mechanisms.

Results

Nuciferine significantly attenuated lipid accumulation and metabolic dysfunction in a hyperlipidemic rat model, with the biosynthesis and metabolism of phenylalanine, tyrosine, and tryptophan as pivotal metabolic pathways. Mechanistically, nuciferine activated intestinal type 2 taste receptor 46 (TAS2R46), promoting Ca²⁺-dependent secretion of glucagon-like peptide-1 (GLP-1). Subsequently, the hepatic GLP-1 receptor was cascaded to upregulate expression of liver X receptor alpha and ATP-binding cassette transporter A1, thereby reducing pathological VLDL overproduction.

Conclusion

This investigation establishes nuciferine’s therapeutic potential in metabolic disorders and hyperlipidemia by activating intestinal TAS2R46 to regulate hepatic VLDL synthesis and secretion.