Citri grandis Exocarpium Extract Alleviates Atherosclerosis in ApoE−/− Mice by Modulating the Expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1

<i>Citri grandis</i> exocarpium (<i>Citri grandis</i>) has been consumed by human beings for fifteen hundred years. It is commonly consumed as a health drink and dietary supplement in China. However, its nutritional and healthcare functions are still not fully understood. <b>Objective:</b> Our previous study found that oral administration of <i>Citri grandis</i> extract can significantly decrease the blood lipid levels of hyperlipidemic mice fed a high-fat diet. The aim of this study was to confirm the preventative effects of <i>Citri grandis</i> extract against atherosclerosis. <b>Methods:</b> Atherosclerotic lesion models were induced in HUVECs and apoE^-/- C57BL/6J mice. ApoE^-/- mice fed a high-fat diet were orally administered <i>Citri grandis</i> extract (0.4, 0.8, and 1.6 g/kg/d BW) and Simvastatin (1 mg/kg/d BW) on the first day of model establishment. After a 16-week treatment, serum samples and aorta and liver tissues were collected. Observation of pathological changes in aortic and liver tissues was performed using a light microscope with oil red O, H&E, Masson's trichrome staining, and TEM. Biochemical detection was employed to determine the serum levels of TC, TG, LDL-C, and HDL-C as well as the activities of AST and ALT. In addition, expression studies of TGF-β, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1 were performed via qPCR and Western blot analysis. <b>Results:</b> Compared with cholesterol-induced HUVECs, <i>Citri grandis</i> extract significantly enhanced cell viability, attenuated the morphological changes in HUVECs, and reduced LDH release. Furthermore, after treatment with <i>Citri grandis</i> extract, the levels of TC, TG, and LDL-C significantly decreased in the atherosclerosis model apoE^-/- mice after 16 weeks, and aortic plaque, lipid deposition, and endothelial injury were obviously ameliorated. The mRNA and protein expression of TGF-β, PPAR-γ, LXR-α, and ABCA1 in aortic and liver of atherosclerosis apoE^-/- mice were upregulated (<i>p</i> < 0.05, <i>p</i> < 0.01), while those of PI3K and Akt1 were suppressed (<i>p</i> < 0.05, <i>p</i> < 0.01). <b>Conclusions:</b><i>Citri grandis</i> extract can significantly decrease the high circulating lipid levels and the liver lipid deposition of high-fat-diet-fed apoE^-/- mice and reduce aorta lipid accumulation and atherosclerotic plaques by regulating the expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1. <i>Citri grandis</i> extract can be used as a healthcare dietary supplement for the prevention of abnormal lipid metabolism and atherosclerosis.