Activation of PPARα lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2

To elucidate the mechanisms underlying the cholesterol lowering effects of PPARα agonists we investigated key regulators of cholesterol synthesis and uptake in rats and in the rat hepatoma cell line Fao after treatment with the PPARα agonists clofibrate and WY 14,643, respectively. In rat liver as well as in Fao cells, PPARα activation led to a decrease of transcriptionally active nuclear SREBP-2. mRNA concentrations of the key regulators of SREBP processing, Insig-1 in rat liver and Insig-1 and Insig-2a in Fao cells, were increased upon PPARα activation. Thus we suggest, that the observed reduction of the amount of nuclear SREBP-2 was due to an inhibition of the processing of the precursor protein. Both, in rat liver and in Fao cells, mRNA concentrations of the SREBP-2 target genes HMG-CoA reductase (EC1.1.1.34) and LDL receptor were reduced after treatment with the PPARα agonists. Furthermore, treatment of Fao cells with WY 14,643 reduced cholesterol synthesis. As a result, the amount of total cholesterol in liver, plasma and lipoproteins of clofibrate treated rats and in WY 14,643 treated Fao cells was decreased compared to control animals and cells, respectively. In conclusion, we could show a novel link between PPARα and cholesterol metabolism by demonstrating that PPARα activation lowers cholesterol concentration by reducing the abundance of nuclear SREBP-2.