Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Nuciferine activates intestinal TAS2R46 to attenuate metabolic disorders and hyperlipidemia via hepatic VLDL regulation.
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Ding Chen, Ruan Jian, Huang Jingxian, Liu Limin, Li Yu, Du Yuan, Zhao Yan
Аннотация
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.
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.