Therefore, it is desirable to develop natural drugs that have cholesterol-lowering effect comparable to statins, but could be tolerated well by the patients. Astragalus polysaccharides, an extract of Radix Astragali, is one of the main efficacious principles. APS-I and APSII are well known to be the major structural components of APS. APS-I consists of arabinose and glucose in a molar ratio of 1:3.45, while APS-II consists of rhamnose, arabinose and glucose in a molar ratio of 1:6.25:17.86. In China, APS has been extensively used to treat viral infection, acute myocarditis, glomerulonephritis, diabetes, tumor, and many other illnesses, with no toxic record in clinic. Previous reports indicated that some dietary soluble polysaccharides lower plasma cholesterol via reduction of intestinal cholesterol absorption or interference with the enterohepatic circulation of bile acids. However, the cholesterol-lowering effect of APS has not been well studied and underlying mechanisms behind are still elusive. Hence, we are here to determine how APS regulates plasma cholesterol and the cholesterol metabolic pathways in hyperlipidemia hamsters. Inhibiting HMG-CoA reductase activity and increasing hepatic LDLR expression are primary mechanisms of statins therapy for hyperlipidemia. Here, we identify a new cholesterol-lowering drug, APS, that effectively reduces plasma cholesterol to levels comparable to that of statins, but may work through different mechanisms. In our study, a 45.8% reduction of TC, 30% reduction of TG, and 47.4% reduction of LDL-C were achieved in hyperlipidemic hamsters after 3-month treatment of APS, similar to statins that lowered LDL-C by 56.5%. Previous study by Wu CZ et al. showed Ogi-Keishi-Gomotsu-To-Ka-Kojin, a Chinese medicine composite that contains a small amount of APS may also exert a hypolipidemic effect in hamsters. Yet they did not make clear which ingredient really works, as Panax ginseng, a crude drug of OKGK was also reported to show antihypercholesterolemic action in human, chicken and rat. The small intestines are implicated in regulating cholesterol homeostasis through affecting cholesterol absorption. An inhibition of intestinal absorption BI-D1870 S6 Kinase? inhibitor results in lower levels of circulating cholesterol. As ezetimibe and sitosterol, which act directly at the level of intestine, lower plasma cholesterol by inhibiting intestinal fractional cholesterol absorption. Our results revealed that APS led to a profound reduction in intestinal cholesterol absorption and a markedly accelerated rate of fecal neutral sterol excretion. Correlation between cholesterol absorption rates and plasma TC or LDL-C concentrations were also observed, suggesting a hitherto unknown mechanism that APS reduces plasma cholesterol by interfering with the intestinal cholesterol absorption.