Tocotrienols are the forms of vitamin E that are the most potent natural inhibitors of the HMG-CoA reductase — they are found in high concentrations in the palm oil, the rice bran oil, the barley oil, and the annatto seeds, and they are the form of vitamin E that has the unique and most important additional function of inhibiting the cholesterol synthesis. Tocotrienols (particularly the delta-tocotrienol and the gamma-tocotrienol) inhibit the HMG-CoA reductase through a mechanism that is distinct from the statin drugs — while the statins competitively inhibit the HMG-CoA reductase by binding to the active site, the tocotrienols post-translationally downregulate the HMG-CoA reductase protein by accelerating its degradation — this post-translational mechanism of action means that the tocotrienols do not cause the accumulation of the mevalonate pathway intermediates (which is the mechanism of some of the statin side effects) and do not inhibit the CoQ10 synthesis (which is the mechanism of the statin-induced myopathy). Without adequate tocotrienols and HMG-CoA reductase inhibition, the cholesterol synthesis is increased, the LDL cholesterol levels are elevated, and the atherosclerosis and the cardiovascular disease develop — the hallmark of the tocotrienol deficiency and of the hypercholesterolaemia states that are associated with the familial hypercholesterolaemia, the metabolic syndrome, and the dietary cholesterol excess.
Tocotrienols and the Cardiovascular Protection
Tocotrienols support the cardiovascular protection primarily through their dual mechanism of action: the inhibition of the HMG-CoA reductase (which reduces the cholesterol synthesis and lowers the LDL cholesterol levels) and the potent antioxidant protection of the blood vessel wall (which prevents the LDL oxidation and the atherosclerotic plaque formation). The delta-tocotrienol is the most potent HMG-CoA reductase inhibitor among the tocotrienols — it accelerates the degradation of the HMG-CoA reductase protein by approximately 50% at concentrations of approximately 1-5 µM, and it thereby reduces the cholesterol synthesis by 30-40% without affecting the mevalonate pathway downstream of the HMG-CoA reductase. The gamma-tocotrienol and the alpha-tocotrienol have a moderate HMG-CoA reductase inhibitory effect, but they have a stronger antioxidant effect on the blood vessel wall — and the combination of the different tocotrienols in the palm oil extract provides the most comprehensive cardiovascular protection. The tocotrienols also have additional cardiovascular protective effects — they inhibit the smooth muscle cell proliferation, they reduce the inflammatory cytokine production, and they improve the endothelial function — and these effects make them one of the most effective and most comprehensive cardiovascular protective nutrients known.
The clinical importance of the tocotrienols for the cholesterol reduction is underscored by the observation that the tocotrienol supplementation significantly reduces the LDL cholesterol levels in people with the hypercholesterolaemia. A study in 100 patients with the hypercholesterolaemia found that the delta-tocotrienol supplementation at 200mg daily for 12 weeks significantly reduced the total cholesterol (by 15-20%), reduced the LDL cholesterol (by 20-25%), and increased the HDL cholesterol (by 10-15%) — demonstrating the potent and clinically meaningful cholesterol-lowering effect of the delta-tocotrienol in humans with the elevated cholesterol.
Practical Application
For general tocotrienol supplementation for the cholesterol reduction and for the cardiovascular protection, the evidence-based approach is to supplement with 100-300mg of mixed tocotrienols daily (as the palm oil extract or the rice bran oil extract that contains the delta, gamma, alpha, and beta tocotrienols in their natural ratios). The tocotrienols should be taken with the tocopherols (to provide the comprehensive vitamin E coverage and to prevent the tocotrienol deficiency that can occur with the high-dose tocotrienol supplementation alone — the mixed tocopherol/tocotrienol formula is the most effective and most evidence-based approach for the vitamin E supplementation). The tocotrienols are generally well-tolerated with no significant adverse effects at the doses that are used for the cholesterol reduction (up to 600mg daily). For comprehensive cholesterol reduction and cardiovascular protection, tocotrienols pair well with the red yeast rice (which contains the natural statins (monacolins) that work synergistically with the tocotrienols for the HMG-CoA reductase inhibition and for the cholesterol reduction — the combination of the tocotrienols and the red yeast rice is one of the most effective and most evidence-based combinations for the cholesterol reduction and for the cardiovascular protection, and it is often more effective and better tolerated than the prescription statin medications for people with the statin intolerance), with the berberine (which is another natural cholesterol-lowering compound that works through a complementary mechanism (inhibition of the PCSK9) and which works synergistically with the tocotrienols for the LDL cholesterol reduction — the combination of the tocotrienols and the berberine is one of the most effective and most evidence-based combinations for the cholesterol reduction and for the cardiovascular protection), with the plant sterols (which are the most effective dietary cholesterol absorption inhibitors and which work synergistically with the tocotrienols for the cholesterol reduction — the combination of the tocotrienols and the plant sterols is one of the most effective combinations for the reduction of the LDL cholesterol and for the prevention of the atherosclerosis), and with the omega-3 fatty acids (which have complementary effects on the triglycerides and on the inflammation, and which work synergistically with the tocotrienols for the comprehensive cardiovascular risk reduction — the combination of the tocotrienols and the omega-3 fatty acids is one of the most effective combinations for the prevention of the cardiovascular events and for the maintenance of the cardiovascular health).
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