Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients

Zulfitri A Mat Daud, Boniface Tubie, Marina Sheyman, Robert Osia, Judy Adams, Sharon Tubie, Pramod Khosla, Zulfitri A Mat Daud, Boniface Tubie, Marina Sheyman, Robert Osia, Judy Adams, Sharon Tubie, Pramod Khosla

Abstract

Purpose: Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population.

Patients and methods: A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1.

Results: TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl-ester transfer protein activity (P<0.001).

Conclusion: TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.

Keywords: end-stage renal disease; hemodialysis; lipid profiles; nutrition intervention; tocotrienol-rich fraction; vitamin.

Figures

Figure 1
Figure 1
Mean changes in plasma TAG normalized to baseline. Notes: Values are presented as mean ± standard error of the mean. TAG data were normalized using baseline values. *Significant difference (P<0.05) compared with placebo at each time point based on independent t-test. At week 16, there was a marginal difference between TRF and placebo groups (P=0.072). Abbreviations: TAG, triacylglycerols; TRF, tocotrienol-rich fraction.
Figure 2
Figure 2
Mean changes in plasma HDLC normalized to baseline. Notes: Values are presented as mean ± standard error of the mean. HDLC data were normalized using baseline values. *Significant difference (P<0.05) compared with placebo at each time point based on independent t-test. Abbreviations: HDLC, high-density lipoprotein cholesterol; TRF, tocotrienol-rich fraction.
Figure 3
Figure 3
Comparison of ApoA1 (A) and CETP activity (B) during week 12 and week 16. Notes: Data are presented as mean ± standard error of the mean. *Significant difference (P<0.05) compared with placebo at each time point, tested by independent t-test. Figure (A) shows plasma ApoA1 concentration during week 12 and week 16 in both groups as measured by ELISA method. Figure (B) shows CETP activity during week 12 and week 16 in both groups as measured in the plasma using fluorometric assay kit. Abbreviations: ApoA1, apolipoprotein A1; CETP, cholesteryl ester transfer protein; ELISA, enzyme-linked immunoabsorbent assay; TRF, tocotrienol-rich fraction.
Figure 4
Figure 4
Pearson’s correlation coefficient in lipid parameters during week 12 and week 16. Notes: (A and B) Correlation between ApoA1 (mg/mL plasma) and HDLC (mg/dL plasma) at week 12 and week 16, respectively. (C and D) Correlation between CETP activity (pmol/μL plasma/hour) and TAG (mg/dL plasma) at week 12 and week 16, respectively. Abbreviations: ApoA1, apolipoprotein A1; CETP, cholesteryl ester transfer protein; HDLC, high-density lipoprotein cholesterol; TAG, triacylglycerols; TRF, tocotrienol-rich fraction.

References

    1. Collins AJ, Foley RN, Herzog C, et al. Excerpts from the US Renal Data System 2009 Annual Data Report. Am J Kidney Dis. 2010;55(1 Suppl 1):S1–S420. A6–A7.
    1. Collins AJ. Cardiovascular mortality in end-stage renal disease. Am J Med Sci. 2003;325(4):163–167.
    1. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116(1):85–97.
    1. Carrero JJ, Stenvinkel P, Cuppari L, et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM) J Ren Nutr. 2013;23(2):77–90.
    1. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62(5):1524–1538.
    1. Vaziri ND. Causes of dysregulation of lipid metabolism in chronic renal failure. Semin Dial. 2009;22(6):644–651.
    1. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003;42(5):864–881.
    1. Galli F, Floridi AG, Floridi A, Buoncristiani U. Accumulation of vitamin E metabolites in the blood of renal failure patients. Clin Nutr. 2004;23(2):205–212.
    1. Riccioni G, N DO, Scotti L, et al. Circulating plasma antioxidants, inflammatory markers and asymptomatic carotid atherosclerosis in end-stage renal disease patients: a case control study. Int J Immunopathol Pharmacol. 2010;23(1):327–334.
    1. Espe KM, Raila J, Henze A, et al. Low plasma alpha-tocopherol concentrations and adverse clinical outcomes in diabetic hemodialysis patients. Clin J Am Soc Nephrol. 2013;8(3):452–458.
    1. Vaziri ND. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. Am J Physiol Renal Physiol. 2006;290(2):F262–F272.
    1. Pennell P, Leclercq B, Delahunty MI, Walters BA. The utility of non-HDL in managing dyslipidemia of stage 5 chronic kidney disease. Clin Nephrol. 2006;66(5):336–347.
    1. Vaziri ND, Liang K, Parks JS. Down-regulation of hepatic lecithin: cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int. 2001;59(6):2192–2196.
    1. Moradi H, Pahl MV, Elahimehr R, Vaziri ND. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl Res. 2009;153(2):77–85.
    1. Vaziri ND, Navab M, Fogelman AM. HDL metabolism and activity in chronic kidney disease. Nat Rev Nephrol. 2010;6(5):287–296.
    1. Jiang Q, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74(6):714–722.
    1. Serbinova E, Kagan V, Han D, Packer L. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Free Radic Biol Med. 1991;10(5):263–275.
    1. Suzuki YJ, Tsuchiya M, Wassall SR, et al. Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry. 1993;32(40):10692–10699.
    1. Frank J, Chin XW, Schrader C, Eckert GP, Rimbach G. Do tocotrienols have potential as neuroprotective dietary factors? Ageing Res Rev. 2012;11(1):163–180.
    1. Azlina MF, Nafeeza MI, Khalid BA. A comparison between tocopherol and tocotrienol effects on gastric parameters in rats exposed to stress. Asia Pac J Clin Nutr. 2005;14(4):358–365.
    1. Wu SJ, Liu PL, Ng LT. Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol Nutr Food Res. 2008;52(8):921–929.
    1. Heng EC, Karsani SA, Abdul Rahman M, Abdul Hamid NA, Hamid Z, Wan Ngah WZ. Supplementation with tocotrienol-rich fraction alters the plasma levels of Apolipoprotein A-I precursor, Apolipoprotein E precursor, and C-reactive protein precursor from young and old individuals. Eur J Nutr. 2013;52(7):1811–1820.
    1. Burdeos GC, Nakagawa K, Kimura F, Miyazawa T. Tocotrienol attenuates triglyceride accumulation in HepG2 cells and F344 rats. Lipids. 2012;47(5):471–481.
    1. Qureshi AA, Sami SA, Salser WA, Khan FA. Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. J Nutr Biochem. 2001;12(6):318–329.
    1. Minhajuddin M, Beg ZH, Iqbal J. Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats. Food Chem Toxicol. 2005;43(5):747–753.
    1. Coombes JS, Fassett RG. Antioxidant therapy in hemodialysis patients: a systematic review. Kidney Int. 2012;81(3):233–246.
    1. Diepeveen SH, Verhoeven GW, Van Der Palen J, et al. Effects of atorvastatin and vitamin E on lipoproteins and oxidative stress in dialysis patients: a randomised-controlled trial. J Intern Med. 2005;257(5):438–445.
    1. Uzum A, Toprak O, Gumustas MK, Ciftci S, Sen S. Effect of vitamin E therapy on oxidative stress and erythrocyte osmotic fragility in patients on peritoneal dialysis and hemodialysis. J Nephrol. 2006;19(6):739–745.
    1. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 1999;55(5):1899–1911.
    1. Carrero JJ, Stenvinkel P. Inflammation in end-stage renal disease – what have we learned in 10 years? Seminars in Dialysis. 2010;23(5):498–509.
    1. Chin SF, Ibahim J, Makpol S, et al. Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: a randomized controlled study. Nutr Metab (Lond) 2011;8(1):42.
    1. Song BL, DeBose-Boyd RA. Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. J Biol Chem. 2006;281(35):25054–25061.
    1. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem. 1993;268(15):11230–11238.
    1. Saghaei M. Random allocation software for parallel group randomized trials. BMC Med Res Methodol. 2004;4:26.
    1. Daud ZA, Tubie B, Adams J, et al. Effects of protein and omega-3 supplementation, provided during regular dialysis sessions, on nutritional and inflammatory indices in hemodialysis patients. Vasc Health Risk Manag. 2012;8:187–195.
    1. Lee JK, Grace KA, Foster TG, et al. How should we measure medication adherence in clinical trials and practice? Ther Clin Risk Manag. 2007;3(4):685–690.
    1. Chun J, Lee J, Ye L, Exler J, Eitenmiller RR. Tocopherol and tocotrienol contents of raw and processed fruits and vegetables in the United States diet. J Food Compost Anal. 2006;19:196–204.
    1. Piironen V, Syvaoja EL, Varo P, Salminen K, Kaivistoinen P. Tocopherols and tocotrienols in Finnish foods: vegetables, fruits and berries. J Agric Food Chem. 1986;34(4):742–746.
    1. Franke AA, Murphy SP, Lacey R, Custer LJ. Tocopherol and tocotrienol levels of foods consumed in Hawaii. J Agric Food Chem. 2007;55(3):769–778.
    1. Garrow JS, Webster J. Quetelet’s index (W/H2) as a measure of fatness. Int J Obesity. 1985;9(2):147–153.
    1. World Health Organization Obesity: Preventing and Managing the Global Epidemic Geneva: World Health Organization; 2000Available from: Accessed October 17, 2013
    1. Bonaccio M, Bonanni AE, Di Castelnuovo A, et al. Low income is associated with poor adherence to a Mediterranean diet and a higher prevalence of obesity: cross-sectional results from the Moli-sani study. BMJ Open. 2012;2(6)
    1. Hung A, Pupim L, Yu C, et al. Determinants of C-reactive protein in chronic hemodialysis patients: relevance of dialysis catheter utilization. Hemodial Int. 2008;12(2):236–243.
    1. Beerenhout CH, Kooman JP, van der Sande FM, Hackeng C, Leunissen KM. C-reactive protein levels in dialysis patients are highly variable and strongly related to co-morbidity. Nephrol Dial Transplant. 2003;18(1):221.
    1. Meuwese CL, Stenvinkel P, Dekker FW, Carrero JJ. Monitoring of inflammation in patients on dialysis: forewarned is forearmed. Nat Rev Nephrol. 2011;7(3):166–176.
    1. Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis. 2000;35(3):469–476.
    1. Blum A, Costello R, Samsel L, et al. Variability of C-reactive protein levels among patients with stable coronary artery disease and on statin therapy. Isr Med Assoc J. 2009;11(10):602–605.
    1. Hodkova M, Dusilova-Sulkova S, Kalousova M, et al. Influence of oral vitamin E therapy on micro-inflammation and cardiovascular disease markers in chronic hemodialysis patients. Ren Fail. 2006;28(5):395–399.
    1. Bogaty P, Brophy JM, Boyer L, et al. Fluctuating inflammatory markers in patients with stable ischemic heart disease. Arch Intern Med. 2005;165(2):221–226.
    1. Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ. Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia. Am J Clin Nutr. 2002;76(6):1237–1243.
    1. Mensink RP, van Houwelingen AC, Kromhout D, Hornstra G. A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations. Am J Clin Nutr. 1999;69(2):213–219.
    1. Kujawa-Szewieczek A, Wiecek A, Piecha G. The lipid story in chronic kidney disease: a long story with a happy end? Int Urol Nephrol. 2013;45(5):1273–1287.
    1. Vaziri ND, Norris KC. Reasons for the lack of salutary effects of cholesterol-lowering interventions in end-stage renal disease populations. Blood Purif. 2013;35(1–3):31–36.
    1. Zaiden N, Yap WN, Ong S, et al. Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion. J Atheroscler Thromb. 2010;17(10):1019–1032.
    1. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006;116(12):3090–3100.
    1. Glass C, Pittman RC, Weinstein DB, Steinberg D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc Natl Acad Sci U S A. 1983;80(17):5435–5439.
    1. Pruijm M, Schmidtko J, Aho A, et al. High prevalence of anti-apolipoprotein/A-1 autoantibodies in maintenance hemodialysis and association with dialysis vintage. Ther Apher Dial. 2012;16(6):588–594.
    1. Pahl MV, Ni Z, Sepassi L, Moradi H, Vaziri ND. Plasma phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase in end-stage renal disease (ESRD) Nephrol Dial Transplant. 2009;24(8):2541–2546.
    1. Aldred S, Sozzi T, Mudway I, et al. Alpha tocopherol supplementation elevates plasma apolipoprotein A1 isoforms in normal healthy subjects. Proteomics. 2006;6(5):1695–1703.
    1. Cacciagiu LD, Gonzalez AI, Gomez Rosso L, et al. HDL-associated enzymes and proteins in hemodialysis patients. Clin Biochem. 2012;45(3):243–248.
    1. Patel V, Rink C, Gordillo GM, et al. Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. J Nutr. 2012;142(3):513–519.
    1. Fairus S, Nor RM, Cheng HM, Sundram K. Alpha-tocotrienol is the most abundant tocotrienol isomer circulated in plasma and lipoproteins after postprandial tocotrienol-rich vitamin E supplementation. Nutr J. 2012;11:5.
    1. Khosla P, Patel V, Whinter JM, et al. Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal. 2006;8(5–6):1059–1068.
    1. Fairus S, Nor RM, Cheng HM, Sundram K. Postprandial metabolic fate of tocotrienol-rich vitamin E differs significantly from that of alpha-tocopherol. Am J Clin Nutr. 2006;84(4):835–842.
    1. Yap SP, Yuen KH, Wong JW. Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status. J Pharm Pharmacol. 2001;53(1):67–71.

Source: PubMed

3
Abonneren