α-Tocopherol modulates the low density lipoprotein receptor of human HepG2 cells

It has been known for over 60 years that the vitamin E (α-tocopherol) status of rabbits can affect their plasma cholesterol concentration. In 1936, Morgulis and Spencer [1] reported that the plasma cholesterol was twofold higher than normal in rabbits made deficient in vitamin E and that dietary replenishment of the vitamin normalised the cholesterol concentration. This effect was later confirmed by others in the rat [2-4] as well as in the rabbit [5-7]. In animal models of diet-induced hypercholesterolaemia, where the animals are not deficient in vitamin E, α-tocopherol supplementation also often decreases plasma cholesterol [8-12]. This is not always the case however; in some studies either no change [13-15] or even an increase [16] in plasma cholesterol was observed. In the rat however, a concomitant deficiency in selenium may be more relevant to increases in plasma cholesterol than the induced deficiency in vitamin E [17]Changes in the plasma cholesterol concentration may result from effects the vitamin has on liver cholesterol metabolism. Hepatic cholesterol synthesis has been found to be increased in vitamin E-deficient rabbits [5] and the conversion of cholesterol into bile acids was observed to be decreased [5,6]. Such an increase in cholesterolgenesis and a decrease in cholesterol catabolism is consistent with the increase in liver cholesterol concentration found in the vitamin E-deficient rat [3,4].There is however no data on the effects of α-tocopherol, the biologically active homologue of vitamin E, [18] on the hepatic low density lipoprotein (LDL) receptor which is well known to play a major role in the control of plasma cholesterol [19,20]. The importance of the LDL receptor is most clearly seen in the human genetic disorder called familial hypercholesterolaemia where a deficiency in the receptor causes high levels of plasma cholesterol which lead to the premature development of atherosclerosis [20]. The LDL receptor is also highly regulated in that va