We investigated whether ginseng regulates lipoprotein metabolism by altering peroxisome proliferator-activated receptor alpha (PPAR alpha)mediated pathways, using a PPAR alpha-null mouse model. Administration of ginseng extract, ginsenosides, and ginsenoside Rf (Rf) to wildtype mice not only significantly increased basal levels of hepatic apolipoprotein (apo) A-I and C-III tnRNA compared with wild-type controls, but also substantially reversed the reductions in mRNA levels of apo A-I and C-III expected following treatment with the potent PPAR alpha ligand Wy14,643. In contrast, no effect was detected in the PPAR alpha-null mice. Testing of eight main ginsenosides on PPAR alpha reporter gene expression indicated that Rf was responsible for the effects of ginseng on lipoprotein metabolism. Furthermore, the inhibition of PPAR alpha-dependent transactivation by Rf seems to Occur at the level of DNA binding. These results demonstrate that ginseng component Rf regulates apo A-I and C-III mRNA and the actions of Rf on lipoprotein metabolism are mediated via interactions with PPAR alpha.. (c) 2005 Elsevier Inc. All rights reserved.