## 4 Associations of Vitamin E with Cardiovascular and Metabolic Diseases
### Tocotrienol  
Tocotrienol belongs to the vitamin E group and consists of a hydrophobic carbon side chain and a 6-chromanol ring with three unsaturated bonds. Tocotrienol is more incorporated in the lipid membrane than tocopherols [66].  
It has been observed that the tootrienol-rich fraction of rice bran oil (RBO) has protective effects on glucose and lipid metabolism. In an experimental study, the administration of tootrienol-rich fractions (TRF), for 6 weeks, decreased the level of TC, LDL-C, TG, apolipoprotein B, and glucose in hypercholesterol swine. In addition, locotrienol in the blood maintained low serum lipid levels, indicating that the alteration of tootropenols to tocopherols is not fast [67].  
In hyperlipidic albino male rats fed an atherogenic diet, TRF, derived from RBO at concentrations of 0, 4, 8, 12, 25, or 50 mg TRF/kg bw/day, reduced plasma TG, TC, and LDL-C. During TRF treatment, the activity of HMG-CoA reductase also decreased [68].  
In diabetic rats, the TRF of RBO and palm oil (PO), administered at a dose of 200 mg/kg bw/day for 8 weeks, showed hypoglycemic effects by lowering fasting blood glucose and HbA1c levels. However, blood glucose was lowered more substantially by treatment with PO-TRF than with RBO-TRF, presumably because RBO has a lower bioavailability due to the higher concentration of tocopherol, which might reduce the bioavailability of tootrienol. In addition, TRF supplementation attenuated renal dysfunction and restored the antioxidant status in diabetic rats [69]. In another in vivo study of a diabetic model, supplement with TRF of RBO and PO improved the glycemic status and lipid parameters. Supplementation with TRF of RBO, at a dose of 400 mg/kg bw/day, and palm oil, at a dose of 200 mg/kg bw/day, reduced HbA1c, blood glucose, VLDL-C, LDL-C, TC, and TG levels compared to the corresponding levels in diabetic control mice. The levels of antioxidant enzymes decreased in the kidneys of diabetic mice groups, but these decreases were attenuated by treatment with RBO and PO-TRF [70]. In addition, TRF, isolated from RBO at a dose of 10 mg/kg bw/day, decreased LDL-C and TC by 30% and 67%, respectively, decreased alkaline phosphatase (ALP) activity, and maintained low activity of glutathione-S-transferase (GST) in the mammary glands and liver of carcinogenic and hypercholesterolemia rats induced by 7,12-dimethylbenz [\(\alpha\)]anthracene (DMBA) [71]. Tocotrienols and bran suppressed body weight gain induced by a HFD, regardless of brain oxidation or serum lipid levels [72].  
Tocotrienols, from heated and stabilized rice bran with a healthy diet, also improved serum lipid profiles in those who have hypercholesterolemia. The subjects were divided into three phases and consumed their typical diet, the American Heart Association Step-1 diet, which was limited to fat intake less than 30% energy and 300 mg/day cholesterol intake, as well as the same diet with capsules of 25 to 200 mg/day of TRF in sequence for 35 days each. As a result, a dose of 100 mg/day TRF decreased serum levels of TG, TC, LDL-C, and apolipoprotein B [14]. In another clinical trial, treatment with tootrienol for 60 days decreased serum LDL-C and TC levels in subjects with T2D and hyperlipidemia [73]. These findings suggest that tootrienols have preventive effects on coronary heart disease, hyperlipidemia, and atherogenesis [14; 73].