In type 2 diabetics, the progression of atherosclerosis is more rapid than the general population and 80% of these patients will die of an atherosclerotic event. Since in these patients hyperglycemia per se confers increased risk for cardiovascular disease (CVD), the presence of even borderline-high-risk LDL-C signals the need for more aggressive LDL-lowering therapy. Most of the lipid lowering agents, currently in use in the treatment of dyslipidemia in type 2 diabetics, have a host of side effects. In contrast, dietary tocotrienols are Vitamin E and have effective lipid lowering property in addition to their potent antioxidant activity. In this study, we have investigated the therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients. Based on known tocotrienol rich fraction (TRF)-mediated decrease on elevated blood glucose and glycated hemoglobin A(1C) (HbA(1C)) in diabetic rats, we have also investigated the effect of TRF on these parameters. A randomized, double blind, placebo-controlled design involving 19 type 2 diabetic subjects with hyperlipidemia was used. After 60 days of TRF treatment, subjects showed an average decline of 23, 30, and 42% in serum total lipids, TC, and LDL-C, respectively. The goal in type 2 diabetics is to reduce LDL-C levels < or = 100mg/dl. In the present investigation tocotrienols mediated a reduction of LDL-C from an average of 179 mg/dl to 104 mg/dl. However, hypoglycemic effect of TRF was not observed in these patients because they were glycemically stable and their glucose and HbA(1) levels were close to normal values. In conclusion, daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.
Dyslipidemia
Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats
Minhajuddin M, Beg ZH, Iqbal J.
Food Chem Toxicol. 2005 May;43(5):747-53.
We investigated a dose-dependent hypolipidemic and antioxidant effect of tocotrienol rich fraction (TRF) isolated from rice bran oil on experimentally induced hyperlipidemic rats. Feeding of atherogenic diet (5% hydrogenated fat, 0.5% cholic acid and 1% cholesterol) for three weeks resulted in a significant increase in plasma triglyceride (3.3-fold) and total cholesterol (2.4-fold) levels. There was a 5-fold increase in the level of LDL cholesterol with only a small increase in HDL cholesterol. On the other hand, HMG-CoA reductase activity was significantly reduced in these animals. The formation of TBARS, thiobarbituric acid reactive substances, (86%) and conjugated dienes (78%) were also significantly higher in these rats compared to normals. After the induction of hyperlipidemia for three weeks, rats were supplemented with different doses of TRF for one week. TRF supplementation decreased the lipid parameters in a dose-dependent manner with an optimum effect at a dose of 8 mg TRF/kg/day. HMG-CoA reductase activity, which was increased after the withdrawal of atherogenic diet, remained significantly decreased during the TRF treatment. Feeding of TRF also decreased TBARS and conjugated dienes significantly. These results suggest that TRF supplementation has significant health benefits through the modulation of physiological functions that include various atherogenic lipid profiles and antioxidants in hypercholesterolemia.
Suppression of 7,12-dimethylbenz[alpha]anthracene-induced carcinogenesis and hypercholesterolaemia in rats by tocotrienol-rich fraction isolated from rice bran oil
Iqbal J, Minhajuddin M, Beg ZH.
Eur J Cancer Prev. 2003 Dec;12(6):447-53.
The anti-tumour and anti-cholesterol impacts of tocotrienol-rich fraction (TRF) were investigated in rats treated with the chemical carcinogen 7,12-dimethylbenz [alpha]anthracene (DMBA), which is known to induce mammary carcinogenesis and hypercholesterolaemia. DMBA administration to rats was associated with the appearance of multiple tumours on mammary glands after 6 months. Alkaline phosphatase (ALP) and glutathione-S-transferase (GST) are used as marker enzymes to monitor the severity of carcinogenesis. Although no tumours were visible on livers, hepatic ALP and GST activities of DMBA-treated rats were profoundly elevated in comparison to enzyme activities of normal control rats. Feeding of TRF (10 mg/kg body weight/day) for 6 months, isolated from rice bran oil (RBO), to DMBA-administered rats, reduced the severity and extent of neoplastic transformation in the mammary glands. Similarly, plasma and mammary ALP activities increased during carcinogenesis (95% and 43%, respectively), were significantly decreased in TRF-treated rats, whereas TRF mediated a further increase of 51% in hepatic ALP activity. TRF treatment to rats maintained low levels of GST activities in liver ( approximately 32%) and mammary glands ( approximately 21%), which is consistent with anti-carcinogenic properties of TRF. Administration of DMBA also caused a significant increase of 30% in plasma total cholesterol and 111% in LDL-cholesterol levels compared with normal control levels. Feeding of TRF to rats caused a significant decline of 30% in total cholesterol and 67% in LDL-cholesterol levels compared with the DMBA-administered rats. The experimental hypercholesterolaemia caused a significant increase in enzymatic activity (23%) and protein mass (28%) of hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase. Consistent with TRF-mediated reduction in plasma lipid levels, enzymatic activity and protein mass of HMG-CoA reductase was significantly reduced. These results indicate that TRF has potent anti-cancer and anti-cholesterol effects in rats.
Nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats: Antioxidant protection by gamma-tocotrienol
Newaz MA, Yousefipour Z, Nawal N, Adeeb N.
J Physiol Pharmacol. 2003 Sep;54(3):319-27.
Involvement of free radicals and nitric oxide (NO) has long been implicated to the pathogenesis of essential hypertension. Several studies using antioxidants as the radical scavenger have shown to confer protection against free radical mediated diseases. This study is designed to investigate the role of antioxidant gamma-tocotrienol on endothelial nitric oxide synthase (NOS) activity in spontaneously hypertensive rats (SHR). SHR’s were divided into four groups namely untreated SHR (HC), treatment with 15 mg gamma-tocotrienol/kg diet (gammal), 30 mg gamma-tocotrienol/kg diet (gamma2) and 150 mg gamma-tocotrienol/kg diet (gamma3) and studied for three months. Wister Kyoto (WKY) rats were used as the control (C). Blood pressure was recorded every fortnightly by tail plethysmography. Animals were sacrificed and NOS activity in blood vessels was measured by [3H]arginine radioactive assay. Nitrite concentration in plasma was determined by Greis assay and lipid peroxides in the blood vessels by spectrofluorometry. This study showed that gamma-tocotrienol significantly reduced systolic blood pressure (SBP) in SHRs with a maximum reduction in group treated with gamma-tocotrienol 15 mg/kg diet (HC: 210 +/- 9 mmHg, gammal:123 +/- 19 mmHg). Blood vessels from untreated SHR showed a reduced NOS activity compare to that of WKY rats (C: 1.54 +/- 0.26 pmol/mg protein, HC: 0.87 +/- 0.23 pmol/mg protein; p<0.001). Gamma-tocotrienol improves NOS activity in all the groups with more significance in group gamma2 (p<0.001) and gamma3 (p<0.05). Plasma level of nitrite was reduced in SHR from 55 +/- 3 microM/ml in WKY to 26+/-2 muM/ml (p<0.001). Plasma nitrite level was reversed by treatment with gamma-tocotrienol. (gammal: p<0.001, gamma2: p<0.005, gamma3: p<0.001, respectively). In all the treatment groups, NOS activity showed significant negative correlation with blood pressure (gammal: r=-0.716, p<0.05; gamma2: r=-0.709, p<0.05; gamma3: r=-0.789, p<0.05). For plasma nitrite, although it shows a negative correlation with blood pressure it was significant only in gammal (r=-0.676, p<0.05) and gamma2 (r=-0.721, p<0.05). From this study we found that compared to WKY rats, SHR has lower NOS activity in blood vessels, which upon treatment with antioxidant gamma-tocotrienol increased the NO activity and concomitantly reduced the blood pressure. These findings further strengthen the hypothesis that free radicals and NO play critical role in pathogenesis of essential hypertension.
Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia
Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ.
Am J Clin Nutr. 2002 Dec;76(6):1237-43.
Background: Tocotrienols have been reported to lower LDL-cholesterol and fasting glucose concentrations and to have potent antioxidant effects, but the results are contradictory.
Objective: The objective was to study the relative effect of tocotrienol supplements of different compositions (mixed alpha- plus gamma-, high gamma-, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F(2alpha), a measure of oxidative stress, in healthy hypercholesterolemic men and women.
Design: This was a double-blind, randomized, parallel-design study in which subjects (n = 67 men and women) consumed 1 of 3 commercially available tocotrienol supplements or a safflower oil placebo for 28 d. Blood and urine samples were obtained before and after the 28-d supplementation phase for analysis of fasting blood lipids, glucose, tocotrienols and tocopherols, and 8-iso-prostaglandin F(2alpha).
Results: Overall, serum tocotrienols were increased in subjects who consumed tocotrienols, which showed that the putatively active components were absorbed. No significant differences in mean lipid or glucose concentrations were observed among the 4 treatment groups at the end of the 28-d supplementation phase. However, when the values were expressed as a percentage change from the concentrations during the presupplementation run-in phase, LDL cholesterol increased slightly (7 +/- 2%) but significantly (P < 0.05) in the group consuming the mixed alpha- plus gamma-tocotrienol supplement when compared with LDL cholesterol in the group consuming the P25-complex tocotrienol. Neither mean concentrations nor the percentage change in 8-iso-prostaglandin F(2alpha) differed significantly among treatments.
Conclusion: Supplementation with 200 mg tocotrienols/d from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.
Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters
Raederstorff D, Elste V, Aebischer C, Weber P.
Ann Nutr Metab. 2002;46(1):17-23.
Background/Aims: Tocotrienols has been shown to inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity; however, the published animal and human studies yield conflicting results. We investigated the effects of a 4-week dietary supplement of either gamma-tocotrienol (86% gamma-T3) or a mixture of tocotrienols (29.5% alpha-T3, 3.3% beta-T3, 41.4% gamma-T3, 0.1% delta-T3: mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet.
Methods: The hamsters were randomized into 7 groups: no treatment, 16 mg/day/kg BW simvastatin, 23, 58, 263 mg/day/kg BW gamma-tocotrienol, and 39 or 263 mg/day/kg BW for the mixture of tocotrienols. Plasma lipid levels were measured after 2 and 4 weeks of treatment.
Results: In all groups treated with tocotrienol total cholesterol levels were decreased, ranging from 7 to 23% after 2 weeks of treatment and from 7 to 15% after 4 weeks. Low-density lipoprotein plasma levels changed accordingly: a decline of 6-37% after 2 weeks and of 12-32% at the end of the study was observed. After 4 weeks of treatment, total cholesterol and low-density lipoprotein plasma levels were significantly reduced in the 263 mg/day/kg BW mixed tocotrienols and the 58 mg/day/kg BW and 263 mg/day/kg BW gamma-tocotrienol groups when compared to the no treatment group. Plasma triglycerides and high-density lipoprotein levels did not change significantly.
Conclusion: This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.
Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans
Qureshi, A. A.,Sami, S. A.,Salser, W. A.,Khan, F. A.
Atherosclerosis, 2002. 161(1): 199-207.
Abstract
Tocotrienols are effective in lowering serum total and LDL-cholesterol levels by inhibiting the hepatic enzymic activity of beta-hydroxy-beta-methylglutaryl coenzymeA (HMG-CoA) reductase through the post-transcriptional mechanism. alpha-Tocopherol, however, has an opposite effect (induces) on this enzyme activity. Since tocotrienols are also converted to tocopherols in vivo, it is necessary not to exceed a certain dose, as this would be counter-productive. The present study demonstrates the effects of various doses of a tocotrienol-rich fraction (TRF25) of stabilized and heated rice bran in hypercholesterolemic human subjects on serum lipid parameters. Ninety (18/group) hypercholesterolemic human subjects participated in this study, which comprised three phases of 35 days each. The subjects were initially placed on the American Heart Association (AHA) Step-1 diet and the effects noted. They were then administered 25, 50, 100, and 200 mg/day of TRF25 while on the restricted (AHA) diet. The results show that a dose of 100 mg/day of TRF25 produce maximum decreases of 20, 25, 14 (P<0.05) and 12%, respectively, in serum total cholesterol, LDL-cholesterol, apolipoprotein B and triglycerides compared with the baseline values, suggesting that a dose of 100 mg/day TRF25 plus AHA Step-1 diet may be the optimal dose for controlling the risk of coronary heart disease in hypercholesterolemic human subjects.
Effects on the human serum lipoprotein profile of beta-glucan, soy protein and isoflavones, plant sterols and stanols, garlic and tocotrienols
Kerckhoffs DA, Brouns F, Hornstra G, Mensink RP.
J Nutr. 2002 Sep;132(9):2494-505
The effects of beta-glucan, soy protein, isoflavones, plant sterols and stanols, garlic and tocotrienols on serum lipoproteins have been of great interest the last decade. From a critical review of the literature, it appeared that recent studies found positive as well as no effects of beta-glucan from oats on serum LDL cholesterol concentrations. These conflicting results may suggest that the cholesterol-lowering activity of products rich in oat beta-glucan depends on factors, such as its viscosity in the gastrointestinal tract, the food matrix and/or food processing. The effects of beta-glucan from barley or yeast on the lipoprotein profile are promising, but more human trials are needed to further substantiate these effects. It is still not clear whether the claimed hypocholesterolemic effects of soy can be attributed solely to the isoflavones. Several studies found no changes in serum LDL cholesterol concentrations after consumption of isolated soy isoflavones (without soy protein), indicating that a combination of soy protein and isoflavones may be needed for eliciting a cholesterol-lowering effect of soy. Therefore, the exact (combination of) active ingredients in soy products need to be identified. The daily consumption of 2-3 g of plant sterols or stanols reduces LDL cholesterol concentrations by 9-14%. It has been demonstrated that functional foods enriched with plant sterols and stanols are effective in various population groups, and in combination with cholesterol-lowering diets or drugs. Whether garlic or garlic preparations can be used as a lipid-lowering agent is still uncertain. It is important to characterize the active components in garlic and their bioavailability after ingestion. It is not very likely that tocotrienols from palm oil or rice bran oil have favorable effects on the human serum lipoprotein profile.
Dose-dependent cholesterolemic activity of tocotrienols
Khor H Dr, Ng T, Rajendran R.
Malays J Nutr. 2002 Sep;8(2):157-166.
Tocotrienols and tocopherols are isoforms of vitamin E. Vitamin E may exhibit antioxidant, prooxidant and non-antioxidant activities depending upon circumstances. In this study, the effect of tocotrienols and a-tocopherol on the activities of HMG CoA reductase and cholesterol 7 a-hydroxylase was investigated. Pure tocotrienols were isolated from palm fatty acid distillate and pure a-tocopherol was obtained commercially. Guinea pigs were treated with different dosages of tocotrienols and a-tocopherol. After the treatment period, animals were sacrificed and liver microsomes were prepared. HMG CoA reductase and cholesterol 7a-hydroxylase were assayed using tracer techniques. Our results showed that the effects of tocotrienols and a-tocopherol on the activities of both the enzymes were dose-dependent. At low dosages, both tocotrienols and a-tocopherol exhibited an inhibitory effect on both the enzymes. Moreover, tocotrienols were a much stronger inhibitors than a-tocopherol. At high dosages, on the other hand, tocotrienols and a-tocopherol showed opposite effects on the enzymes. While tocotrienols continued to exhibit an inhibitory effect, a-tocopherol actually exhibited a stimulatory effect on both the enzymes. A possible explanation for this observation is suggested.
Rice bran oil and gamma-oryzanol in the treatment of hyperlipoproteinaemias and other conditions
Cicero AF, Gaddi A.
Phytother Res. 2001 Jun;15(4):277-89.
Diet is the first (and sometimes the only) therapeutic approach to hyperlipoproteinaemias. Rice bran oil and its main components (unsaturated fatty acids, triterpene alcohols, phytosterols, tocotrienols, alpha-tocopherol) have demonstrated an ability to improve the plasma lipid pattern of rodents, rabbits, non-human primates and humans, reducing total plasma cholesterol and triglyceride concentration and increasing the high density lipoprotein cholesterol level. Other potential properties of rice bran oil and gamma-oryzanol, studied both in vitro and in animal models, include modulation of pituitary secretion, inhibition of gastric acid secretion, antioxidant action and inhibition of platelet aggregation. This paper reviews the available data on the pharmacology and toxicology of rice bran oil and its main components with particular attention to those studies relating to plasma lipid altering effects.