Esculetin promotes HDL-driven cholesterol excretion involved in CD36-mediated phagocytosis of adipose tissue macrophages and CEBPbeta
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ABSTRACT: Postprandial dyslipidemia is a recognized risk factor for atherosclerosis. High-density lipoprotein (HDL)-mediated reverse cholesterol transport plays a crucial role in mitigating this risk by clearing postprandial lipids. This study aimed to investigate the impact of esculetin, a 4-Hydroxycoumarin, on postprandial cholesterol metabolism and excretion after a high-fat meal. Esculetin significantly elevated postprandial HDL cholesterol levels in serum and postprandial bile acid levels in bile, and altered serum metabolomics in mice fed a high-fat meal, indicating esculetin promotes HDL-driven cholesterol excretion after a high-fat meal. Furthermore, esculetin administration in mice led to an increase in the ratio and phagocytic activity of a subset of adipose tissue macrophages (ATMs) expressing high levels of CD36 and Tim4. Inhibition of CD36 by Sulfo-N-succinimidyl oleate (SSO) blocked esculetin-induced elevation of postprandial serum HDL and bile acid levels in bile. Additionally, esculetin demonstrated the ability to increase the uptake of oxidized LDL (ox-LDL) via CD36 in a macrophage cell line, which might involve alteration of the epigenetic landscape controlled by CCAAT enhancer-binding protein beta (C/EBPβ). Esculetin-induced increased uptake of ox-LDL and elevation of CD36 was inhibited in C/EBPβ-deficient cells. A relatively higher expression of C/EBPβ was observed in CD36+ ATMs, and esculetin increased the ratio of C/EBPβ+ CD36+ ATMs in mice fed a lipid-rich meal. Moreover, the direct interaction between esculetin and C/EBPβ were observed by Terahertz chemical microscope. Overall, these findings suggest esculetin promotes HDL-mediated postprandial cholesterol excretion by directly binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.
ORGANISM(S): Mus musculus
PROVIDER: GSE234771 | GEO | 2024/06/12
REPOSITORIES: GEO
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