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Aim Sini decoction (SND) is a commonly used herbal formula showing lipid-lowering effects and is applied in traditional Chinese medicine (TCM) for the treatment of cardiovascular disease (CVD) and atherosclerosis (AS). However, the mechanisms behind its anti-atherosclerotic effects are still unknown, and will be investigated in this study. Methods AS was induced in rabbits by high fat diet (HFD) and treated with solvent (HFD group), atorvastatin (Ator group), or SND (SND group) for 12 weeks. Healthy rabbits (Chow group) were used as control. Serum and liver homogenates were collected, and lipid profiles as well as serum ApoA-I and ApoB were examined. Histopathological changes and lipid deposition in the proximal aorta and liver were detected by Oil red O staining. Western blot was used to detect the expression of ABCA1, ApoA-I, ApoB, PPARγ, and LXRα in liver, peritoneal macrophages, peripheral mononuclear cells (PMC), and adipose tissues. Results SND significantly attenuated the levels of total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol(LDL-C) in serum and liver. However, high density lipoprotein cholesterol (HDL-C) dramatically increased. SND treatment also decreased lipid deposition and improved the structure of the liver and aorta. Furthermore, SND enhanced the expression levels of ABCA1, PPARγ, and LXRα in liver, adipose tissues, PMC, and peritoneal macrophages. It also upregulated hepatic and serum ApoA-I expression and serum ApoA-I/ApoB ratio. CONCLUSIONS:SND treatment relieved AS, improved lipid profiles, and increased serum HDL-C level. The potential mechanism behind this might be the improvement of reverse cholesterol transport (RCT) involved with enhanced expression of ABCA1, ApoA-I, PPARγ, and LXRα.