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The antihyperlipidaemic effect and potential mechanisms of Schisandra chinensis fruit extract were investigated in hamsters fed with a high-fat diet. Treating with SF extract significantly decreased the serum levels of total cholesterol, triacylglycerol and low-density lipoprotein cholesterol, alleviated insulin resistance, attenuated inflammation and declined liver lipid accumulation. The expression and activities of key lipid-metabolic regulators were altered to the lipid-lowering side. Screening of different fractions of SF extract for lipid-lowering activities revealed that the lignan-rich fraction was the most effective. Eight abundant lignans were isolated from the major active fraction of SF extract, in which schisandrols A, B and schisandrins B, C showed significant lipid-lowering effects in HepG2 cells, and schisandrin C was potent in decreasing the blood lipids in Triton WR-1339 induced hyperlipidaemic mice. Overall, these results indicated that the extract and lignans in SF were effective regulators of lipogenesis and could be useful for treating hyperlipidaemia.