The Alpha-tocopherol Transfer Protein and Vitamin E Adequacy

Maret G. Traber, Ph.D.
Associate Professor of Nutrition
LPI Principal Investigator

Scott W. Leonard
LPI Research Assistant


Summary: A protein synthesized in the liver preferentially selects the natural form of vitamin E for distribution to the tissues. A special mouse strain without this protein and highly susceptible to atherosclerosis developed lesions larger and more complex than those in mice susceptible to atherosclerosis that have the protein. Measurements of lipid oxidation in the mice suggest that vitamin E inhibits atherosclerosis through its antioxidant properties. Taken together, these studies indicate that long-term optimal intake of vitamin E in humans may protect against heart disease.

Millions of Americans use vitamin E supplements. Most vitamin E supplements contain synthetic alpha-tocopherol, but unlike other vitamins, synthetic vitamin E is not identical to natural. Alpha-tocopherol (alpha-tocopherol) is present in nature in only one form, RRR-alpha-tocopherol. The chemical synthesis of alpha-tocopherol results in eight different forms, only one of which is RRR-alpha-tocopherol. Chemically synthesized vitamin E is known as all rac-alpha-tocopherol. These forms differ in that they can be “right” or “left” (R or S) at three different places in the alpha-tocopherol molecule. The most important place is what’s known as the 2-position—half of the synthetic is 2R and half is 2S (see diagram).

To add to the confusion, vitamin E supplements are labeled d-alpha for natural and dl-alpha for synthetic. To study how the body uses natural or synthetic vitamin E, we used chemically labeled forms containing deuterium as tracers. Deuterium is a stable, non-radioactive isotope of hydrogen that is used as a chemical tracer to study chemical reactions and the movement and deposition of chemicals in the body. When we fed equal amounts of deuterium-labeled natural and synthetic vitamin E to humans, both plasma and tissues subsequently contained twice as much natural as synthetic vitamin E. This difference is thought to arise from differences of the affinity of the hepatic alpha-tocopherol transfer protein (alpha-TTP) for the various forms, with a preference for the 2R-alpha-tocopherol forms. 

In humans, all vitamin E forms are absorbed in the intestine. The majority of the absorbed vitamin E is delivered to the liver, where the naturally occurring form of vitamin E, RRR-alpha-tocopherol, is preferentially secreted into the circulation for delivery to tissues. Importantly, humans with ataxia from vitamin E deficiency have defects in the alpha-TTP. These people become vitamin E deficient because they are unable to secrete alpha-tocopherol into the circulation. However, because the amounts and activities of alpha-TTP have not been measured in the patients’livers, the functions of alpha-TTP have remained incompletely understood. Moreover, the mechanisms for the regulation of vitamin E in tissues are not known. This led us todevelop a genetic model of vitamin E deficiency byeliminating the alpha-TTP gene in mice in order to characterize the function of the protein coded for by the gene. The alpha-TTP-null mice lack the alpha-TTP found in normal mice.

We used the alpha-TTP-null mice to test whether alpha-TTP is responsible for maintaining plasma alpha-tocopherol concentrations. We also wanted to determine if alpha-TTP influences the observed preference for natural RRR-alpha-tocopherol. Even though a human genetic mutation has produced a very small population of people who lack the alpha-TTP, alpha-TTP-null mice were used for these experiments because we were able to perform well-controlled experiments that cannot be performed with humans. We hypothesized that alpha-TTP preferentially selects the 2R-alpha-tocopherol forms of vitamin E for secretion into plasma and delivery to tissues. We analyzed 17 different tissues to evaluate whether alpha-tocopherol can accumulate despite the deficiency of hepatic alpha-TTP. Mice were fed diets that contained deuterium-labeled natural and synthetic vitamin E in a one-to-one ratio. After the mice consumed the diet for 3 months, 85% of the vitamin E in their tissues was found to be labeled. In the mice deficient in alpha-TTP, the levels of vitamin E in plasma and tissues were extremely low compared to normal mice. In tissues from the normal mice, the ratio of natural to synthetic vitamin E was 2 to 1, but in the alpha-TTP-null mice there were equal, small amounts of natural and synthetic vitamin E in tissues. These data suggest that alpha-tocopherol concentrations are highly dependent upon the function of alpha-TTP and that this protein preferentially selects only the 2R-alpha-tocopherol forms from all rac-alpha-tocopherol for secretion into plasma. In the normal mice with alpha-TTP, the enrichment of tissues with natural vitamin E appears to be due to uptake of alpha-tocopherol from the plasma, which contained twice as much natural as synthetic vitamin E. 

In another study we recently published in the Proceedings of the National Academy of Sciences, we used the alpha-TTP-null mice to study the relationship between vitamin E and atherosclerosis. Many experts believe that a high plasma vitamin E concentration protects against atherosclerosis, but the results from clinical intervention studies published thus far have been equivocal. In our study, alpha-TTP-null mice were bred with a mouse strain that is very susceptible to atherosclerosis. These “double-null” mice were then used to test the hypothesis that a decrease in plasma vitamin E caused by alpha-TTP deficiency would promote atherosclerosis. 

The mice were fed a chow diet that was low fat and generally adequate for mice for 30 weeks. As expected, we found that alpha-TTP-null mice had plasma and tissue alpha-tocopherol concentrations only about 15% of the levels in normal control mice. We then measured the area of the atherosclerotic lesions. The lesion areas in the double-null mice were about 36% larger than in the controls that were susceptible to atherosclerosis but not deficient in alpha-TTP. The aortic lesions in the double-null mice consistently had more complex lesions with necrotic cores, cholesterol crystals, and a fibrous cap. Plasma cholesterol, vitamin C, and urate levels were similar in the double-null mice and controls.

To study the relationship between atherosclerotic lesion development and lipid oxidation, we analyzed aortic levels of total F2-isoprostanes, which are substances used as a sensitive measure of lipid oxidation. Total F2-isoprostanes were found to be 2-fold higher in the double-null mice compared to controls, suggesting that vitamin E inhibits atherosclerosis through its antioxidant properties.

It now appears that vitamin E can help prevent atherosclerosis and that its deficiency will accelerate but not cause atherosclerosis. Our second mouse study was important in understanding the role of vitamin E in heart disease because there is no clear evidence demonstrating how vitamin E may actually be beneficial in preventing or decreasing cardiovascular disease. It is known that vitamin E protects fats from oxidizing, but now we also have an in vivo model showing that not only is there increased fat oxidation when animals are vitamin E deficient but also that vitamin E is necessary to protect against atherosclerotic lesion formation. Since similar mechanisms are likely to occur in humans, it seems reasonable to suppose that vitamin E will help counter oxidative stress and protect us from atherosclerosis.

Calculation of the amount of alpha-tocopherol in vitamin E supplements:
For RRR-alpha-tocopherol (natural or d-alpha-tocopherol) Multiply the IU x 0.67 
Example:
100 IU of natural vitamin E = 67 mg of natural vitamin E 
For all-rac-alpha-tocopherol (synthetic or dl-alpha-tocopherol) Multiply the IU x 0.45
Example:
100 IU of synthetic vitamin E = 45 mg of natural vitamin E

For more information on vitamin E, see the Linus Pauling Institute's Micronutrient Information Center.

Last updated May, 2001
 


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