Four Citrus Flavanones Exert Atherosclerosis Alleviation Effects in ApoE-/- Mice via Different Metabolic and Signaling Pathways

Citrus flavanones have the potential to alleviate atherosclerosis. The metabolism and anti-atherosclerosis signaling pathways of four citrus flavanones (naringin, naringenin, hesperidin, and hesperetin) were compared in ApoE(-/-) mice. Naringin had the most potent anti-atherogenic effect, followed by hesperidin, naringenin, and hesperetin with reductions of 55.92, 34.98, 42.87, and 24.70% in the atherosclerotic plaque rate compared with the control, respectively. Oral naringin mainly existed in the intestine due to the high water solubility of 7-O-nohesperidoside and alleviated atherosclerosis mainly by enhancing bile acid synthesis in the gut microbiota-FXR/FGF15-CYP7A1 pathway. The other three flavanones mainly alleviated atherosclerosis in the liver after absorption from the intestine. Hesperidin upregulates ABCA1 by 1.8-fold to enhance cholesterol reverse transport, while the aglycones naringenin and hesperetin inhibited cholesterol synthesis via downregulating HMGCR by 2.4- and 2.3-fold, respectively. Hesperetin was more resistant to absorption than naringenin due to the existence of a 4'-methoxyl group and had relatively weak effects on atherosclerosis. The alleviation of atherosclerosis by the four citrus flavanones was tightly related to differences in their in vivo metabolism and signaling pathways. This provides new insights into the anti-atherosclerotic mechanisms of food functional flavanones and guidance for the design of novel, efficient strategies for preventing atherosclerosis based on citrus flavanones.

Automated summary

Citrus flavanones have been shown to have the potential to alleviate atherosclerosis, with naringin exhibiting the strongest anti-atherosclerotic effect. Naringin is mainly present in the intestine and alleviates atherosclerosis by enhancing bile acid synthesis, while the other three flavanones act mainly in the liver after absorption. This study provides insights into the differences in metabolism and signaling pathways of citrus flavanones in vivo and their effects on atherosclerosis, offering guidance for the development of novel strategies for preventing atherosclerosis.