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Esculetin modulates postprandial cholesterol metabolism involved in phagocytosis of adipose tissue macrophages (RNA-Seq)

ABSTRACT: Postprandial dyslipidemia is a significant risk factor for atherosclerotic cardiovascular diseases. High-density lipoprotein (HDL)-driven reverse cholesterol transport (RCT) plays a crucial role in clearing postprandial lipids. In this study, we aimed to investigate the role of esculetin, a hypolipidemic substance, in regulating postprandial cholesterol metabolism. We measured postprandial cholesterol levels and conducted metabolomics and transcriptomics studies to understand the effect and underlying mechanism of esculetin on postprandial cholesterol metabolism in mice fed a lipid-rich meal. We found that esculetin significantly elevated the postprandial HDL cholesterol levels and induced alterations in postprandial serum metabolomics and hepatic transcriptomics which involved in the key steps of HDL-driven RCT including lipid metabolism, ABC transporters and bile acid biosynthesis and secretion. Additionally, the ratio and the phagocytic activity of an adipose tissue macrophage subset highly expressing CD36 and Tim4 increased following esculetin administration in mice. CCAAT enhancer-binding protein beta (C/EBPβ), a key transcription factor, was involved in the effect of esculetin on macrophages phagocytosis in ox-LDL-stimulated macrophages cells. Therefore, esculetin appears to elevate postprandial HDL levels and regulate postprandial cholesterol metabolism which are associated with the increased phagocytosis of adipose tissue macrophages and C/EBPβ.

ORGANISM(S): Mus musculus

PROVIDER: GSE276565 | GEO | 2025/04/21

REPOSITORIES: GEO

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Project description:Rationale: Exogenous lipid metabolism, influenced by dietary intake, contributes to postprandial dyslipidemia. Adipose tissue macrophages (ATMs) mediate the phagocytosis of postprandial lipids from the exogenous diet, generating high-density lipoprotein (HDL) particles that facilitate lipid circulation and excretion. However, the underlying mechanisms remain poorly understood. This study investigates the effects of esculetin, a coumarin compound, on postprandial cholesterol circulation and excretion following a high-fat meal. Methods: Mice were fed a lipid-rich meal for three days to assess the effects of esculetin on postprandial lipid circulation, using serum lipid profiling and metabolomics analysis. Epididymal white adipose tissue (eWAT) removal and flow cytometry were performed to analyze ATMs and confirm their role in mediating esculetin’s effects on postprandial lipemia. Epigenetic profiling, transcriptome analysis, chromatin immunoprecipitation, and Terahertz chemical microscopy were employed to elucidate the molecular targets and mechanisms of esculetin. Results: Esculetin significantly elevates postprandial HDL cholesterol levels to values comparable to pitavastatin and modifies serum metabolites involved in bile-mediated cholesterol excretion, leading to increased bile acid concentrations in the bile. This effect is mediated by an increased ratio and phagocytic activity of a subset of ATMs expressing the scavenger receptor CD36, as eWAT removal and CD36 blockade inhibit this response. Furthermore, esculetin enhances the uptake of oxidized LDL via CD36, as demonstrated in cultured macrophages, and induces epigenetic changes controlled by the key transcription factor C/EBPβ, accompanied by increased C/EBPβ binding to the Cd36 promoter. A direct interaction between esculetin and C/EBPβ was observed using Terahertz chemical microscopy. Additionally, the activation of C/EBPβ by esculetin in ATMs was confirmed in vivo. Conclusion: Esculetin accelerates postprandial lipid circulation by binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.

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Esculetin modulates postprandial cholesterol metabolism involved in phagocytosis of adipose tissue macrophages (RNA-Seq)

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