Natural Tocotrienols

A. Cholesterol Lowering Effects

• 1. The structure of an inhibitor of cholesterol biosynthesis isolated from barley

  Qureshi A. et al. (1986), "The structure of an inhibitor of cholesterol biosynthesis isolated from barley." J.Biol.Chem., 261(23) : 10544-50.

  Purification of the oily, nonpolar fraction of high protein barley (Hordeum vulgare L.) flour by high pressure liquid chromatography yielded 10 major components, two (I, II) of which were potent inhibitors of cholesterogenesis in vivo and in vitro. The addition of purified inhibitor I (2.5-20 ppm) to chick diets significantly decreased hepatic cholesterogenesis and serum total and low density lipoprotein cholesterol and concomitantly increased lipogenic activity. The high resolution mass spectrometric analysis and measurement of different peaks of inhibitor I gave a molecular ion at m/e 424 (C29H44O2) and main peaks at m/e 205, 203, and 165 corresponding to C13H17O2, C13H15O2, and C10H13O2 moieties, respectively. which are characteristic of d-alpha-tocotrienol. This identification was confirmed against synthetic samples. The tocotrienols are widely distributed in the plant kingdom and differ from tocopherols (vitamin E) only in three double bonds in the isoprenoid chain which appear to be essential for the inhibition of cholesterogenesis.

• 2. Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2 and platelet factor 4 in pigs with inherited hyperlipidemias

  Qureshi A. et al. (1991), "Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2 and platelet factor 4 in pigs with inherited hyperlipidemias." Am. J Clin Nutr., 53 : 1042S - 1046S.

  Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.

• 3. Tocotrienols in the treatment of hypercholesterolemia, hyperlipidemia and thromboembolic disorders

  Qureshi A. et al. (1994), “United States Patent Number : 5,348,974 : Tocotrienols in the treatment of hypercholesterolemia, hyperlipidemia and thromboembolic disorders”. Assignee : Bristol-Myers Squibb Co. New York.

  This invention relates to the use of tocotrienol, gamma-tocotrienol and delta-tocotrienol in reducing hypercholesterolemia, hyperlipidemia and thromboembolic disorders in mammals. The isolation of these tocotrienols from natural sources and their chemical synthesis is disclosed. The present invention also relates to prodrugs and pharmaceutical compositions of gamma-tocotrienol, delta-tocotrienol and tocotrienol and uses thereof.

• 4. Tocotrienols and tocotrienol-like compounds and methods for their use

  Qureshi A. et al. (1997), "United States Patent Number : 5,919,818 : Tocotrienols and tocotrienols-like compounds and methods for their use.” Assignee : Lipogenics, Inc, Scottsdale, Arizona.

  The present invention relates to novel tocotrienols and tocotrienol-like compounds displaying biological activity. The tocotrienols and tocotrienol-like compounds of this invention may be conveniently obtained from biological sources or by chemical synthesis and may be used in pharmaceutical compositions, foodstuffs and dietary supplements. This invention also relates to the use of tocotrienols, tocotrienol-like compounds, and mixtures thereof, as hypocholesterolemic, antithrombotic, antioxidizing, antiatherogenic, antiinflammatory and immunoregulatory agents, or as agents useful to decrease lipoprotein (a) concentration in the blood or to increase feed conversion efficiency.

• 5. gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets

  Watkins, T. et al. (1993), “Gamma-Tocotrienol as Hypocholesterolemic and Antioxidant Agent in Rats Fed Atherogenic Diets”. Lipids, 28 (12) : 1113-1118.

  This study was designed to determine whether incorporation of gamma-tocotrienol or alpha-tocopherol in an atherogenic diet would reduce the concentration of plasma cholesterol, triglycerides and fatty acid peroxides, and attenuate platelet aggregability in rats. For six weeks, male Wistar rats (n = 90) were fed AIN76A semisynthetic test diets containing cholesterol (2% by weight), providing fat as partially hydrogenated soybean oil (20% by weight), menhaden oil (20%) or corn oil (2%). Feeding the ration with menhaden oil resulted in the highest concentrations of plasma cholesterol, low and very low density lipoprotein cholesterol, triglycerides, thiobarbituric acid reactive substances and fatty acid hydroperoxides. Consumption of the ration containing gamma-tocotrienol (50 mg/kg) and alpha-tocopherol (500 mg/kg) for six weeks led to decreased plasma lipid concentrations. Plasma cholesterol, low and very low density lipoprotein cholesterol, and triglycerides each decreased significantly (P < 0.001). Plasma thiobarbituric acid reactive substances decreased significantly (P < 0.01), as did the fatty acid hydroperoxides (P < 0.05), when the diet contained both chromanols. Supplementation with gamma-tocotrienol resulted in similar, though quantitatively smaller, decrements in these plasma values. Plasma alpha-tocopherol concentrations were lowest in rats fed menhaden oil without either chromanol. Though plasma alpha-tocopherol did not rise with gamma-tocotrienol supplementation at 50 mg/kg, gamma-tocotrienol at 100 mg/kg of ration spared plasma alpha-tocopherol, which rose from 0.60 +/- 0.2 to 1.34 +/- 0.4 mg/dL (P < 0.05). The highest concentration of alpha-tocopherol was measured in plasma of animals fed a ration supplemented with alpha-tocopherol at 500 mg/kg.

   

• 6. Synergistic Effect of Tocotrienol-rich Fraction (TRF 25) of Rice Bran and Lovastatin on Lipid Parameters in Hypercholesterolemic Humans

  Qureshi A. et al. (2001). “Synergistic Effect of Tocotrienol-rich Fraction (TRF 25) of Rice Bran and Lovastatin on Lipid Parameters in Hypercholesterolemic Humans.” J. Nutr. Biochem. 12(6) : 318-29.

  Tocotrienols exert hypocholesterolemic action in humans and animals. Lovastatin is widely used for that purpose. Both agents work by suppressing the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase through different mechanisms, post-transcriptional vs competitive inhibition. A human study with 28 hypercholesterolemic subjects was carried out in 5 phases of 35 days each, to check the efficacy of tocotrienol-rich fraction (TRF(25)) of rice bran alone and in combination with lovastatin. After placing subjects on the American Heart Association (AHA) Step-1 diet (phase II), the subjects were divided into two groups, A and B. The AHA Step-1 diet was continued in combination with other treatments during phases III to V. Group A subjects were given 10 mg lovastatin, 10 mg lovastatin plus 50 mg TRF(25), 10 mg lovastatin plus 50 mg alpha-tocopherol per day, in the third, fourth, and fifth phases, respectively. Group B subjects were treated exactly to the same protocol except that in the third phase, they were given 50 mg TRF(25) instead of lovastatin.The TRF(25) or lovastatin plus AHA Step-1 diet effectively lower serum total cholesterol (14%, 13%) and LDL-cholesterol (18%, 15% P < 0.001), respectively, in hypercholesterolemic subjects. The combination of TRF(25) and lovastatin plus AHA Step-1 diet significantly reduces of these lipid parameters of 20% and 25% (P < 0.001) in these subjects. Substitution of TRF(25) with alpha-tocopherol produces insignificant changes when given with lovastatin. Especially significant is the increase in the HDL/LDL ratio to 46% in group (A) and 53% (P < 0.002) in group (B). These results are consistent with the synergistic effect of these two agents. None of the subjects reported any side-effects throughout the study of 25-weeks. In the present study, the increased effectiveness of low doses of tocotrienols (TRF(25)) as hypocholesterolemic agents might be due to a minimum conversion to alpha-tocopherol. The report also describes in vivo the conversion of gamma-[4-3H]-, and [14C]-desmethyl (d-P(21)-T3) tocotrienols to alpha-tocopherol.

• 7. Effects of administration of alpha-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity

  Khor HT. et al. (2000). “Effects of Administration of alpha-Tocopherol and Tocotrienols on Serum Lipids and Liver HMG Co-A Reductase Activity. Int’l. J. Food Sci. Nutr. 51 : S3-S11.

  Male hamsters were fed on semi-synthetic diets containing commercial corn oil (CO), isolated corn oil triglycerides (COTG), COTG supplemented with 30 ppm of alpha-tocopherol (COTGTL) and COTG supplemented with 81 ppm of alpha-tocopherol (COTGTH) as the dietary lipid for 45 days. Male albino guinea pigs were fed on commercial chow pellets and treated with different dosages of tocopherol and tocotrienols intra-peritoneally for 6 consecutive days. Serum and liver were taken for analysis. Our results show that stripping corn oil of its unsaponifiable components resulted in COTG which yielded lower serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and raised high-density lipoprotein cholesterol (HDL-C) and serum triglycerides (TG) levels. These results indicate that the COTG with its fatty acids are responsible for the hypocholesterolemic effect exhibited by corn oil. However, supplementing the COTG diet with alpha-tocopherol (alpha-T) at 30 ppm significantly raised the serum TC, LDL-C and TG levels, but did not alter the HDL-C level, indicating that alpha-T is hypercholesterolemic. Supplementing the COTG diet with alpha-T at 81 ppm raised the serum TC level but to a lesser extent as compared to that obtained with 30-ppm alpha-T supplementation. The increased TC, in this case, was reflected mainly by an increased in HDL-C level as the LDL-C level was unchanged. The TG level was also raised but to a lesser extent than that obtained with a lower alpha-T supplementation. The liver HMG CoA reductase (HMGCR) activity was exhibited (56%) by the COTG as compared to CO. Supplementation of alpha-T at 30 ppm to the COTG diet resulted in further inhibition (76%) of the liver HMGCR activity. On the contrary, supplementation of alpha-T at 81 ppm to COTG diet resulted in a highly stimulatory effect (131%) on the liver HMGCR activity. Short-term studies with guinea pigs treated intra-peritoneally with alpha-T showed that at low dosage (5 mg) the HMGCR activity was inhibited by 46% whereas increasing the dosage of alpha-T to 20 mg yielded lesser inhibition (18%) as compared to that of the control. Further increase in the dosage of alpha-T to 50 mg actually resulted in 90% stimulation of the liver HMGCR activity as compared to the control. These results clearly indicate that the effect of alpha-T on HMGCR activity was dose-dependent. Treatment of the guinea pigs with 10 mg of tocotrienols (T3) resulted in 48% inhibition of the liver HMGCR activity. However, treatment with a mixture of 5 mg of alpha-T with 10 mg of T3 resulted in lesser inhibition (13%) of the liver HMGCR activity as compared to that obtained with 10 mg of T3. The above results indicate that the alpha-T is hypercholesterolemic in the hamster and its effect on liver HMGCR is dose-dependent. T3 exhibited inhibitory effect on liver HMGCR and alpha-T attenuated the inhibitory effect of T3 on liver HMGCR.

• 8. Vitamin E and Factors Affecting Atherosclerosis in Rabbit Fed with A Cholesterol-Rich Diet

  Nafeeza MI. et al. (2000). “Vitamin E and Factors Affecting Atherosclerosis in Rabbit Fed with A Cholesterol-Rich Diet.” Intl. J. Food Sci. Nutr. 51 : S79-S94.

  The present study aims to examine the effects of a palm-oil-derived vitamin E mixture containing tocotrienol (approximately 70%) and tocopherol (approximately 30%) on plasma lipids and on the formation of atherosclerotic plaques in rabbits given a 2% cholesterol diet. Eighteen New Zealand White rabbits (2.2-2.8 kg) were divided into three groups; group 1 (control) was fed a normal diet, group 2 (AT) was fed a 2% cholesterol diet and group 3 (PV) was fed a 2% cholesterol diet with oral palm vitamin E (60 mg/kg body weight) given daily for 10 weeks. There were no differences in the total cholesterol and triacylglycerol levels between the AT and PV groups. The PV group had a significantly higher concentrations of HDL-c and a lower TC/HDL-c ratio compared to the AT group (P < 0.003). The aortic tissue content of cholesterol and atherosclerotic lesions were comparable in both the AT and PV groups. However, the PV group had a lower content of plasma and aortic tissue malondialdehyde (P < 0.005). Our findings suggest that despite a highly atherogenic diet, palm vitamin E improved some important plasma lipid parameters, reduced lipid peroxidation but did not have an effect on the atherosclerotic plaque formation.

• 9. Effect of Squalene, Tocotrienols, and alpha-Tocopherol Supplementations in The Diet on Serum and Liver Lipids in The Hamster

  Khor HT. et al. (1997). “Effect of Squalene, Tocotrienols, and alpha-Tocopherol Supplementations in The Diet on Serum and Liver Lipids in The Hamster.” Nutr. Res. 17(3) : 475-83.

  The short-term effect of dietary squalene (SQ) tocotrienols (T3) and α-tocopherol (T) on serum and liver cholesterol levels was investigated in the hamster. Our results show that dietary squalene (0.1%) lowered serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) levels as compared with the control palm oil triacylglycerol (POTG) group; however, only the difference between serum TC levels of the two groups was significant (P<0.05). In the presence of 162 ppm of tocotrienols or 72 ppm of α-tocopherol the serum TC and LDL-C levels of squalene-fed hamsters were further lowered (P<0.01) as compared with that of the POTG and POTG-SQ groups; the HDL-C level appeared unaffected. As for the serum TAG level, the effect of squalene, tocotrienols and α-tocopherol were inconsistent. The liver total lipids of the squalene-fed (POTG-SQ), squalene and T3-fed (POTG-SQ-T3) and squalene and α-tocopherol-fed (POTG-SQ-T) hamsters were significantly increased as compared to that of the POTG group. This increase in total lipids was due to significant increases in TC and Cholesterol ester (CE) levels in the liver of the treated groups as compared with the control group (POTG). Liver TAG level was not affected consistently in treated groups. Our results show that short-term low-level (0.1%) squalene feeding lowered serum cholesterol levels by increasing cholesterol ester accumulation in the liver. Tocotrienols and α-tocopherol enhanced the serum cholesterol-lowering effect of dietary squalene without increasing further the cholesterol ester accumulation activity in the liver of the hamster.

• 10. Novel Tocotrienols of Rice Bran Modulate Cardiovascular Disease Risk Parameters of Hypercholesterolemic Humans

  Qureshi A. et al. (1997). “Novel Tocotrienols of Rice Bran Modulate Cardiovascular Disease Risk Parameters of Hypercholesterolemic Humans." J. Nutr Biochem 8(5) : 290-8.

  Tocotrienols inhibit cholesterol synthesis by post-transcriptionally suppressing β-hydroxy-β-methylglutaryl-coenzyme A reductase activity. A double blind, 12-week study was performed to investigate the effect of a novel tocotrienol-rich fraction (TRF25; obtained by molecular distillation from specially processed rice bran oil) on cardiovascular disease risk factors of hypercholesterolemic human subjects (serum total cholesterol >5.69 mmol/L). After acclimation to an alcohol-free regimen (baseline) participants were assigned to the National Cholesterol Education Program (NCEP) Step-1 diet (saturated fat <19%, total fat <30% of total calories and cholesterol <7.76 mmol/L). The participants were evaluated after 4 weeks of exposure to the NCEP Step-1 diet; one group of 21 participants was continued on the NCEP Step-1 diet for 4 weeks receiving an additional 1.2 gm corn oil (placebo group) and a second group of 20 received 200 mg TRF25 dissolved in 1.0 gm corn oil (TRF225 group). Serum total cholesterol and LDL-cholesterol levels of all the participants, stable during the baseline phase of the study, decreased 5% and 8%, respectively, during the 4-week NCEP Step-1 diet. Placebo continuing on the NCEP Step-1 diet for an additional 4 weeks experienced additional but modest decreases in serum total cholesterol (2%) and LDL-cholesterol (3%), yielding significant (P < 0.05) decreases when compared with the baseline values. These responses confirm the cholesterol-lowering action of a low fat, low cholesterol diet. Participants receiving TRF25 had 12% and 16% reductions (P < 0.05) in total cholesterol and LDL-cholesterol levels during the 4-week experimental phase; during the two phases (NCEP Step-1 diet plus treatment) the serum total cholesterol and LDL-cholesterol levels of these participants were decreased (P < 0.05) by 17% and 24%, respectively. TRF25-mediated decreases in Apo B, Lp(a), platelet factor 4 and thromboxane B2 (15%, 17%, 14%, and 31%, respectively) were significant (P < 0.05). There was no change in the levels of HDL-cholesterol and apoliproprotein A-I by this treatment. The treatments also resulted in remarkable increases in the levels of LDL-bound antioxidants, especially tocotrienols, which have substantially greater antioxidant activity than vitamin E.

• 11. Response of Hypercholesterolemic Subjects to Administration of Tocotrienols

  Qureshi A. et al. (1995). “Response of Hypercholesterolemic Subjects to Administration of Tocotrienols.” Lipids. 30(12) : 1171-7.

  The cholesterol-suppressive actions of Palmvitee and gamma-tocotrienol were assessed in hypercholesterolemic subjects after acclimation to the American Heart Association Step 1 dietary regimen for four and eight weeks, respectively. The four-week dietary regimen alone elicited a 5% decrease (P < 0.05) in the cholesterol level of the 36 subjects. Subjects continuing on the dietary regimen for a second four-week period experienced an additional 2% decrease in their cholesterol levels. Dietary assessments based on unanticipated recalls of 24-h food intake records suggest that significant reductions in energy and fat, predominantly in saturated fat, intakes are responsible. The subjects experienced significant Palmvitee- and gamma-tocotrienol-mediated decreases in cholesterol. The group of subjects acclimated to the dietary regimen for four weeks responded to Palmvitee (a blend of tocols providing 40 mg alpha-tocopherol, 48 mg alpha-tocotrienol, 112 mg gamma-tocotrienol, and 60 mg delta-to-cotrienol/day for four weeks) with a 10% decrease in cholesterol (P < 0.05). Dietary assessments showed no further change in energy and fat intakes. alpha-Tocopherol attenuated the cholesterol-suppressive action of the tocotrienols. The second group of subjects, acclimated to the dietary regimen for eight weeks, received 200 mg gamma-tocotrienol/d for four weeks. The cholesterol-suppressive potency of this alpha-tocopherol-free preparation was calculated to be equivalent to that of the mixture of tocotrienols (220 mg) used in the prior study. Cholesterol levels of the 16 subjects in the second group decreased 13% (P < 0.05) during the four-week trial. Plasma apolipoprotein B and ex vivo generation of thromboxane B2 were similarly responsive to the tocotrienol preparations, whereas neither preparation had an impact on high density lipoprotein cholesterol and apolipoprotein A-1 levels.

• 12. Tocotrienols Inhibit Liver HMG CoA Reductase Activity in the Guinea Pig

  Khor HT. et al. (1995). “Tocotrienols Inhibit Liver HMG CoA Reductase Activity in the Guinea Pig.” Nutr. Res. 15(4) : 537-44.

  Male guinea pigs were treated intraperitoneally with different dosages of tocotrienols isolated from palm oil fatty acid distillate (PFAD) for 6 consecutive days. Control animals were treated with vitamin E-free palm oil triglycerides. Commercial animal pellets and water were given ad libitum during the treatment period. The guinea pigs were sacrificed at around 2400 hr. Liver HMG CoA reductase was assayed by a combination of conventional TLC and liquid scintillation spectrophotometry using 14C-HMG CoA as the substrate. Our results show that tocotrienols isolated from PFAD inhibited liver HMG CoA reductase activity in the guinea pig and the inhibitory effect of tocotrienols on HMG CoA reductase appeared to be dose-dependent. Analysis of the serum tocol profiles indicate that only α-tocopherol was found in the serum and there was no tocotrienol in the serum after 6 consecutive treatments with tocotrienols. These results indicate a rapid clearance of tocotrienols from the blood circulation. On the contrary, the liver retained much of the tocotrienols administered. The levels of tocotrienols in the liver appear to increase with increased dosages of tocotrienols in the treatment.

• 13. Tocotrienols Regulate Cholesterol Production in Mammalian Cells by Post-Transcriptional Suppression of 3-Hydroxy-3-Methylglutaryl CoA Reductase

  Parker RA. et al. (1993). “Tocotrienols Regulate Cholesterol Production in Mammalian Cells by Post-Transcriptional Suppression of 3-Hydroxy-3-Methylglutaryl CoA Reductase.” J. Biol. Chem. 268(15) : 11230-8.

  Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of 14Cacetate but not 3H mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by 35Smethionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.

• 14. Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols

  Pearce BC. et al. (1992). “Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols.” J. Med. Chem. 35(20) : 3595-606.

  Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

• 15. Protective effects of vitamin E against hypercholesterolemia-induced age-related diseases

  Catalgol, B. & Ozer, N. K. (2011). Protective effects of vitamin E against hypercholesterolemia-induced age-related disease. Genes & Nutrition. 7: 91-98

  Hypercholesterolemia is a major risk factor for age-related diseases such as atherosclerosis and Alzheimer’s disease (AD). Changes in human plasma cholesterol levels results from the interaction between multiple genetic and environmental factors. The accumulation of excess cholesterol in blood vessels leads to atherosclerosis. Many studies on this field show that differential expression of oxidative stress-related proteins, lipid metabolism-related enzymes, and receptors response to atherogenic diet. Additionally, excess brain cholesterol has been associated with increased formation and deposition of amyloid-β peptide from amyloid precursor protein which may contribute to the risk and pathogenesis of AD. To consider genetically, more than 50 genes have been reported to influence the risk of late-onset AD. Some of these genes might be also important in cholesterol metabolism and transport. Epidemiological studies have shown an association between high intake and high serum concentrations of antioxidant vitamins like vitamin E and lower rates of ischemic heart diseases. It has been known that vitamin E also inhibits smooth muscle cell proliferation by non-antioxidant mechanism. On the basis of the previous results, vitamin E has been accepted as an important protective factor against hypercholesterolemia-induced age-related diseases.