Citrus polymethoxylated flavones modulate the biosynthesis of cholesterol and triacylglycerols via multiple mechanisms. Tangeretin inhibits the activities of diacylglycerol acyltransferase and of microsomal triglyceride transfer protein, as well as activates the membrane peroxisome proliferator-activated receptor in human hepatoma HepG2 cells. These modulatory effects subsequently inhibit the assembly and secretion of apolipoprotein B-containing lipoproteins, such as the very low-density lipoprotein (VLDL) and the low-density lipoprotein (LDL). Nobiletin, but not tangeretin, inhibited macrophage acetylated LDL metabolism linked to the action of the specific class A scavenger receptor. This inhibitory effect blocked the formation of macrophage foam-cells, which are essential to atherosclerotic plaque formation. In hamster feeding trials the polymethoxylated flavones dramatically lowered serum total cholesterol, LDL+VLDL cholesterol, as well as the levels of serum triacylglycerols. Total liver concentrations of tangeretin derivatives corresponded to hypolipidemic concentrations of
intact tangeretin in earlier in vitro studies. If similar actions occur in humans, these compounds may be viable alternatives
to the statin drugs to combat elevated cholesterol and triacylglycerols.