CARDIOVASCULAR BENEFITS OF TOCOTRIENOLS
Barrie Tan, Ph.D.; Anne Mueller, MSc
American River Nutrition, Inc.
I. What are the components of vitamin E supplements?
Tocotrienol and tocopherol, the two forms of the vitamin E family, are similar in that both have the same head called chromanol nucleus, which is the site of their well-known antioxidant activities. Tocotrienol and tocopherol differ in the molecule’s tail. Tocotrienol has a shorter farnesyl tail containing double bonds that downregulate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol synthesis. Tocopherol, on the other hand, has a longer phytyl tail without double bonds. Alpha, beta, gamma, and delta are among the isomers of tocotrienol as well as tocopherol. For tocotrienol, the potency of cholesterol inhibition by these isomers is as follows: delta>gamma >alpha>beta.
The isomers of tocotrienols differ depending on the substitution and location of methyl groups at the head region of the molecule. Desmethyl tocotrienols (tocotrienols with less methyl groups) are more active, especially in the absence of a methyl group at C5 position on the chromanol ring system. Delta- and gamma-tocotrienol are the only two isomers that fit this molecular formula. Delta-tocotrienol is known to be monomethylated at C8 position of the chromanol ring system, making it the least substituted, and therefore the most potent isomer of the four tocotrienol compounds.
II. Why are Annatto Tocotrienols superior to tocopherol and other tocotrienol supplements?
Tocopherols do not have the cholesterol-lowering ability that tocotrienols do. In fact, alpha-tocopherol has been shown to attenuate or interfere with the cholesterol-lowering action of tocotrienols.1 The majority of vitamin E supplements contain mostly tocopherols (and for that, mostly alpha-tocopherol) and only traces of tocotrienols, and large clinical studies on alpha-tocopherol’s benefits to cardiovascular health have been equivocal.
Preparations effective in cholesterol-lowering consist of less than 15-20% alpha tocopherol and more than 60% gamma- and delta-tocotrienol, whereas less effective or ineffective preparations consist of more than 30% alpha-tocopherol and less than 45% of gamma- and delta-tocotrienol. This has been supported by clinical studies in which supplements with high alpha-tocopherol content did not contribute to the lowering of cholesterol,2,3 whereas supplements containing low amounts of alpha-tocopherol and high amounts of gamma- and delta-tocotrienol led to a significant decrease in total and LDL cholesterol.4,5
In addition, tocotrienols absorbed better than tocopherols,6 and alpha-tocopherol (if present with other E vitamers) has been shown to prevent absorption of tocopherols and tocotrienols.7
Tocotrienols, although found in low amounts in the American diet (naturally in oils and fats, whole foods, and some processed foods) are most abundant in palm, rice, and annatto. Rice contains about 50% tocotrienols and 50% tocopherols, whereas palm contains approximately 75% tocotrienols and 25% tocopherols. Annatto ranks highest in tocotrienol content, since its tocotrienol content is 100%, and it is virtually tocopherol-free.
A.C. Grace’s tocotrienol product contains the wholesome rainforest annatto derived (not palm sourced) tocotrienols that have the highest concentration of the most effective component of tocotrienols – delta-tocotrienol – using a patented solvent-free extraction method. Annatto tocotrienol contains 90% delta-tocotrienol and 10% gamma-tocotrienol, and better yet, it is tocopherol-free.
III. How does tocotrienol work?
The mechanism of tocotrienol’s hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase,8 and specifically modulates the intracellular mechanism for controlled degradation of the reductase protein9 in charge of cholesterol synthesis.
Ubiquitination, the inactivation of a protein by attaching a ubiquitin to it is an important stage in the degradation of HMG-CoA reductase. As a ubiquitin is attached to the HMG-CoA reductase, the molecule is tagged for transport to the proteasome, a multi-protein complex where degradation occurs. Just recently it has been reported that only gamma- and delta-tocotrienol stimulate the ubiquitination and degradation of the HMG-CoA reductase. In addition, gamma- and delta-tocotrienol block processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that modulate transcription of genes encoding cholesterol biosynthetic enzymes and LDL receptor. Blocking SREBP processing may have implications on the triglyceride synthesis (or reduction) with importance in prediabetic and diabetic conditions.
Other forms of vitamin E (all four tocopherols and alpha- and beta-tocotrienols) do not degrade, down regulate, or block SREBP processing.10
IV. What are the Cardiovascular Benefits of Tocotrienol?
1. Hypercholesterolemia: Recently, animal studies supported results found in earlier cell line studies. Animals whose diet was supplemented with gamma- and delta-tocotrienols showed the greatest decrease in cholesterol levels (32% total and 66% LDL cholesterol), whereas alpha-tocopherol had no effect on cholesterol-lowering. In this study, HDL/LDL cholesterol ratios were improved by 123-150%. The safe dose of various tocotrienols for human consumption is estimated to be 200-1,000mg/day.11
In humans, two open studies7 measured fasting blood lipids before and 2 months after supplementation with annatto tocotrienol (75mg/day) supplementation. In both groups, total cholesterol levels dropped 13%, whereas LDL cholesterol dropped 9-15% and HDL cholesterol increased by 4-7%. The LDL/HDL ratio was reduced by 12-21%. Amongst others, a study conducted by Bristol-Myers Squibb found that after 4-week supplementation with gamma- and delta-tocotrienol (100mg/day) total cholesterol was reduced by 15-22%, and LDL cholesterol was decreased by 10-20%.12
2. Hypertriglyceridemia: An estimated 16% of US residents, 47 million, have metabolic syndrome.13 Some of the defining hallmarks of metabolic syndrome include increased waist circumference, increased serum triglyceride levels, high blood pressure (hypertension), elevated serum glucose, and insulin resistance.14,15 Tocotrienols, especially gamma- and delta-tocotrienols, increase vascular and cardiometabolic integrity and lead to improved management of metabolic syndrome.
Studies on rats in which diabetes was induced showed a significant decrease of cardiometabolic events. Increase of serum advanced glycosylation end-products (AGE) was prevented, while a decrease in blood glucose and glycated hemoglobin was observed.16 In addition, rice bran oil containing tocotrienols lowered plasma triglyceride levels, LDL cholesterol, and hepatic triglyceride concentration, therefore suppressing hyperlipidemic and hyperinsulinemic responses in diabetic rats.17
In several clinical studies with metabolic syndrome patients or patients with diabetes, even small amounts of tocotrienol derived from rice bran were shown to reduce the symptoms associated with the disease. Rice bran water solubles reduced hyperglycemia, glycosylated hemoglobin, and increased insulin levels, while rice bran fiber reduced hyperlipidemia in both type 1 and type 2 diabetics.18
In another large clinical study, vitamin E intake from diet was associated with reduced risk of type 2 diabetes.19 In patients with type 2 diabetes, progression of atherosclerosis is more rapid, and 80% of patients die of atherosclerotic events. In addition, LDL-lowering therapies normally prescribed for patients with diabetes have many side-effects, creating a need for alternative treatment. Tocotrienols, which have no known side-effects, were shown to decrease serum total lipids by 23%, total cholesterol by 30%, and LDL-cholesterol by 42% (from 179mg/dL to 104mg/dL) within 60 days in type 2 diabetics.20 Supplementation of 75mg/day delta-tocotrienol in a small open study was found to promote metabolic health, where triglyceride levels dropped 20-30%.7
3. Atherosclerosis: One of the first steps of atherogenesis is fatty streak formation in arteries, which begins with the adherence of circulating monocytes to the endothelium. Tocotrienols have been shown to reduce cellular adhesion molecule expression and monocytic cell adherence.21 In particular, delta- tocotrienol showed the most profound inhibitory effect on monocytic cell adherence as compared to tocopherols and other tocotrienol isomers.22 It has been suggested that this phenomenon occurs via inhibition of vascular cell adhesion molecule, VCAM-1 expression by delta-tocotrienol.23
Another step in atherogenesis is the formation of unstable plaques, which occurs when platelets aggregate at the site of plaque formation on blood vessel walls, forming clots and eventually blocking the blood flow through arteries. In a human double-blind cross over study, delta-tocotrienol was shown to be significantly more potent in the inhibition of platelet aggregation than the other tocotrienol isomers, giving an overall inhibition of 71%, as compared to 5-37% with other tocotrienols.24 The effects of tocotrienols on atheroma formation have also been compared in animals. Mice fed an atherogenic diet and were given desmethyl tocotrienols had 60% lower plasma cholesterol than the control group on the same diet without supplementation, and the size of atherosclerotic lesions was reduced 10-fold. Alpha-tocopherol, on the other hand, had no effect. This finding was further corroborated in a similar independent study, where desmethyl tocotrienols inhibited atherosclerotic lesions in hyperlipidemic mice.
Atherosclerotic lesion size in mice supplemented with desmethyl tocotrienols was decreased by 42%, whereas with alpha-tocopherol, lesion size was only decreased by 11%.25 Similarly, following supplementation with palm-derived tocotrienols, the size of atherosclerotic lesions in mice was 92-98% smaller than in the alpha-tocopherol and control groups.26 Fully methylated tocotrienols and tocopherols do not have the cardiovascular benefits characteristic of desmethyl tocotrienols.27
A 4-year study on patients with carotid artery arteriosclerosis, the blocking of the artery supplying oxygen to the brain, showed that tocotrienol supplementation caused regression of carotid atherosclerosis. In 88% of patients that took the supplement carotid artery stenosis was regressed or stabilized. Of the control group receiving a placebo, 60% deteriorated, and only 8% improved.28,29 Interestingly, total cholesterol decreased 14% and LDL cholesterol fell 21% in the third and fourth year of the study.30
4. Lipid Peroxidation and Hypertension: Antioxidants play an important role in slowing the process of atherosclerosis, especially by preventing oxidation of LDL. Vitamin E is widely known for its antioxidant properties.31 The antioxidant efficiency of tocotrienols was evaluated as the ability of the compounds to inhibit lipid peroxidation, reactive oxygen species (ROS) production, and heat shock protein expression. Delta-tocotrienol was found to have the greatest antioxidant properties among the tocotrienol isomers,32 which is due to the decreased methylation of the chromanol ring that allows the molecule to be more easily incorporated into cell membranes.7 A comparative in vitro study showed that gamma- and delta-tocotrienol was 4-fold more efficient as scavenger of peroxyl radicals than other tocotrienol isomers.33
Hypertension, elevated blood pressure, can cause damage to arterial walls, making them more susceptible to plaque formation. In recent animal studies tocotrienols were shown to lower blood pressure. When hypertensive rats were treated with gamma-tocotrienol for three months, plasma and blood vessel lipid peroxides were reduced, and total antioxidant status was improved.34 Gamma tocotrienol was shown to reduce systolic blood pressure significantly, and improved nitric oxide synthase activity (NOS), both of which play a critical role in the pathogenesis of essential hypertension.35 Tocotrienol’s impact on hypertension was confirmed in humans, where tocotrienol-rich vitamin E supplementation resulted in significant reductions in their aortic systolic blood pressure, as well as a 9.2% improvement in total antioxidant status.36
V. Summary
Tocotrienols possess powerful cholesterol-lowering properties that are not exhibited by tocopherols.37 Research also shows that high levels of alpha tocopherol may attenuate the bioavailability and functional activity of other vitamin E isomers.4 Desmethyl tocotrienols such as gamma- and delta tocotrienol were found to be much more bioactive than fully methylated tocotrienols and tocopherols. Gamma- and delta-tocotrienol are powerful heterogeneous antioxidants working at the surface of cells. Loss of vascular integrity and hypercoagulability (e.g. adhesion molecules, platelet aggregation, ROS, and NOS¯) is responsible for a plethora of cardiometabolic disorders (e.g. cholesterol, triglyceride) that are characteristic of prediabetes and diabetes. Tocotrienols, especially gamma- and delta-tocotrienols, improve vascular and cardiometabolic integrity which may result in managing hypertension, diabetes,38 metabolic syndrome, and atherosclerosis.
References
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