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

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/EBPß), 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/EBPß. Overall design: To the transcriptomic alterations induced by esculetin in the liver, esculetin (0 or 180mg/kg/d) were daily administered to the mice by oral gavage for 7 days. In the first 4 days, the mice were fed with a control diet (CD) containing 10% kcal from fat. Then the mice were fed with a high- fat diet (HFD) containing 60% kcal from fat for additional 3 days to understand lipid-rich meals-induced postprandial lipid circulation.