Nutraceuticals in hypercholesterolaemia: an overview

Antonello Santini, Ettore Novellino, Antonello Santini, Ettore Novellino

Abstract

Growing attention is now being given to the possible preventive/alternative ways to avoid illness onset. Changes in lifestyle and food habits are taking over from the conventional pharmaceutical-based approach, especially for chronic pathologies. Nutraceuticals have been proposed as key tools for the prevention and cure of some pathological conditions. This is leading research to develop new formulations based on these pharma-foods addressed in a specific way to prevent and cure health issues, which, in turn, will have an effect on therapy-related costs sustained by any National Health Organization. According to existing regulations, nutraceuticals cannot be categorized as either food or drugs but, by definition, often inhabit a grey area in between the two, being assimilated into food supplements, notwithstanding the beneficial properties that they can provide for some pathological conditions. A nutraceuticals-based approach for health management, in particular for some pathological conditions, has resulted in a worldwide growing 'nutraceutical' revolution. An outstanding example is the approach to the 'metabolic syndrome', which includes overweight, obesity and cardiovascular-related diseases, causing a sort of cascade of chronic health conditions, which is becoming a norm in modern life. Hypercholesterolaemia is one of these. It represents an example of a pathology that can be linked to both a poor lifestyle and dietary habits. The nutraceutical approach to hypercholesterolaemia is described in the present review as a possible alternative to the conventional drug-based therapy.

Linked articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
The key players that must be substantiated before the clinical use of nutraceuticals in therapy.
Figure 2
Figure 2
Nutraceutical development pathway.
Figure 3
Figure 3
Hypercholesterolaemia: possible alternative approaches.

References

    1. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ (2008). Statins for secondary prevention in elderly patients. J Am Coll Cardiol 51: 37–45.
    1. Agostoni C, Bresson JL, Fairweather‐Tait S, Flynn A, Golly I, Korhonen H et al. (2011a). Scientific opinion on the substantiation of health claims related to monacolin K from red yeast rice and maintenance of normal blood LDL cholesterol concentrations (ID 1648, 1700) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J 9: 2304–2320.
    1. Agostoni C, Bresson JL, Fairweather‐Tait S, Flynn A, Golly I, Korhonen H et al. (2011b). Scientific opinion on the substantiation of health claims related to beta‐glucans from oats and barley and maintenance of normal blood LDL‐cholesterol concentrations (ID 1236, 1299), increase in satiety leading to a reduction in energy intake (ID 851, 852), reduction of post‐prandial glycaemic responses (ID 821, 824), and “digestive function” (ID 850) pursuant to Article 13(1) of Regulation (EC) No 1924/20061. EFSA J 9: 2207.
    1. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024–6109.
    1. Alonso‐Salces RM, Ndjoko K, Queiroz EF, Ioset JR, Hostettmann K, Berrueta LA et al. (2004). On‐line characterisation of apple polyphenols by liquid chromatography coupled with mass spectrometry and ultraviolet absorbance detection. J Chromatogr A 1046: 89–100.
    1. Amiot MJ, Riva C, Vinet A (2016). Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes Rev 17: 573–586.
    1. Anderson JW, Tietyen‐Clark J (1986). Dietary fiber: hyperlipidemia, hypertension, and coronary heart disease. Am J Gastroenterol 81: 907–919.
    1. ANSES (2014). Opinion of the French Agency for Food, Environmental and Occupational Health & Safety on the risks associated with the presence of “red yeast rice” in food supplements. Request No. 2012‐SA‐0228, 34 pp.
    1. Avis Du Conseil Superieur De La Sante N° 9312 (2016). Compléments alimentaires à base de «levure de riz rouge». 20 pp.
    1. Avula B, Cohen PA, Wang Y, Sagi S, Feng W, Zweigenbaum J et al. (2014). Chemical profiling and quantification of monacolins and citrinin in red yeast rice commercial raw materials and dietary supplements using liquid chromatography‐accurate QToF mass spectrometry: chemometrics application. J Pharm Biomed Anal 100: 243–253.
    1. Baye K, Guyot JP, Mouquet‐Rivier C (2015). The unresolved role of dietary fibers on mineral absorption. Crit Rev Food Sci Nutr In press. doi:.
    1. Bazzano LA, He J, Ogden LG, Loria CM, Whelton PK (2003). Dietary fiber intake and reduced risk of coronary heart disease in US men and women the National Health and Nutrition Examination Survey I epidemiologic follow‐up study. Arch Intern Med 163: 1897–1904.
    1. Berger A, Jones PJH, Abumweis SS (2004). Plant sterols: factors affecting their efficacy and safety as functional food ingredients. Lipids Health Dis 3: 1–19.
    1. Bloch A, Thomson CA (1995). Position of The American Dietetic Association (phytochemicals and functional foods). J Am Diet Assoc 95: 493–496.
    1. Bohn T (2014). Dietary factors affecting polyphenols bioavailability. Nutr Rev 72: 429–452.
    1. Brendan ME, Smith RJ, Hiatt WR (2015). Reducing LDL with PCSK9 Inhibitors. The clinical benefit of lipid drugs. New Engl J Med 373: 1588–1591.
    1. Brown L, Rosner B, Willett WW, Sacks FM (1999). Cholesterol‐lowering effects of dietary fiber: a meta‐analysis. Am J Clin Nutr 69: 30–42.
    1. Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y et al. (2006). Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 47: 1281–1288.
    1. Bursill CA, Abbey M, Roach PD (2007). A green tea extract lowers plasma cholesterol by inhibiting cholesterol synthesis and upregulating the LDL receptor in the cholesterol‐fed rabbit. Atherosclerosis 193: 86–93.
    1. BVL/BfArM . Bundesamt für Verbraucherschutz und Lebensmittelsicherheit (BVL) und das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (2016). . (accessed 7/6/2016).
    1. Chait A, Eckel RH (2016). Lipids, Lipoproteins, and Cardiovascular Disease: Clinical Pharmacology Now and in the Future. J Clin Endocrinol Metab 101: 804–814.
    1. Chen CH, Yang JC, Uang YS, Lin CJ (2013). Improved dissolution rate and oral bioavailability of lovastatin in red yeast rice products. Int J Pharm 444: 18–24.
    1. Christina AB, Paul DR (2006). Modulation of cholesterol metabolism by the green tea polyphenol (−)‐epigallocatechin gallate in cultured human liver (HepG2) cells. J Agr Food Chem 54: 1621–1626.
    1. Cicero FG, Parini A, Rosticci M (2015). Nutraceuticals and cholesterol‐lowering action. IJC Metab Endocr 6: 1–4.
    1. Colonna S, Fulk G, Marangoni F (2013). The food for the health In: The health foods, Springer edn. Milan: Italy, pp. 211–220.
    1. Dàvalos A, Fernàndez‐Hernando C, Cerrato F, Martìnez‐Botas J, Gòmez‐Coronado D, Gòmez‐Cordovès Lasunciò MA (2006). Red grape juice polyphenols alter cholesterol homeostasis and increase LDL‐receptor activity in human cells in vitro. J Nutr 136: 1766–1773.
    1. DeBose‐Boyd RA, Ou J, Goldstein JL, Brown MS (2001). Expression of sterol regulatory element‐binding protein 1c (SREBP‐1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci U S A 98: 1477–1482.
    1. DeFelice SL (1995). The nutraceutical revolution: its impact on food industry R&D. Trends Food Sci Technol 6: 59–61.
    1. Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, Jäkel M et al. (2010). The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J Nutr 140: 1615–1620.
    1. Directive 2002/46/EC (2002). European parliament and of the council on the approximation of the laws of the member states relating to food supplements. Official J L 183: 51–57.
    1. Dong H, Zhao Y, Fuer L (2013). The effects of berberine on blood lipids: a systematic review and meta‐analysis of randomized controlled trials. Planta Med 79: 437–446.
    1. DSHEA (1994). United States Food and Drug Administration (FDA). Dietary Supplement Health and Education Act (DSHEA). U.S. Department of Health and Human Services. United States. Public Law 103–417. Available at FDA website: ; (accessed 7/6/2016).
    1. EFSA Scientific Opinion (2011). EFSA J 9: 2207–2228.
    1. ESCO (2012). European Food Safety Authority scientific cooperation report. Compendium of botanicals reported to contain naturally occurring substances of possible concern for human health when used in food and food supplements. EFSA J 10: 2663–2723.
    1. European Commission (2014). Amending Regulation (EC) No 1881/2006 as regards maximum levels of the contaminant citrinin in food supplements based on rice fermented with red yeast. Monascus purpureus. L67/3–67/4.
    1. European Parliament and Council Regulation (EU) 2015/2283 (2015). Regulation of the 25 November 2015 on novel foods, amending regulation (EU) no 1169/2011 of the European Parliament and of the Council and replacing the regulation (EC) no 258/97 of the European Parliament and of the Council, and the Commission Regulation (EC) No 1852/2001.
    1. Fan D, Wu X, Dong W, Sun W, Li J, Tang X (2013). Enhancement by sodium caprate and sodium deoxycholate of the gastrointestinal absorption of berberine chloride in rats. Drug Dev Ind Pharm 39: 1447–1456.
    1. FDA (2006). Federal Register: May 22, 2006 (volume 71, number 98). Internet: http:// .
    1. GenLiang Y, Li J, Guang Ling Y (2015). Experimental study on acute toxicity of tea polyphenols. J Food Saf Qual 6: 3730–3733.
    1. Gerards M, Terlou RJ, Yu H, Koks CHW, Gerdes VEA (2015). Traditional Chinese lipid‐lowering agent red yeast rice results in significant LDL reduction but safety is uncertain ‐ A systematic review and meta‐analysis. Atherosclerosis 2: 415–423.
    1. Gylling H, Plat J, Turley S, Ginsberg HN, Ellegård L, Jessup W et al. (2014). Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. (2014). Atherosclerosis 232: 346–360.
    1. Hardy G (2000). Nutraceuticals and functional foods: introduction and meaning. Nutrition 16: 688–689.
    1. Harnly J (2016). Importance of accurate measurements in nutrition research: dietary flavonoids as a case study. Adv Nutr 7: 375–382.
    1. Health claims : soluble fiber from certain foods and risk of coronary heart disease (CHD); 2008. [21 CFR sect. 101.81].
    1. Heber D, Yip I, Ashley JM, Elashoff DA, Go VLW (1999). Cholesterol lowering effects of a proprietary Chinese red‐yeast‐rice dietary supplemement. Am J Clin Nutr 69: 231–236.
    1. Henning SM, Niu TY, Liu Y, Lee NH, Hara Y, Thames GD et al. (2005). Bioavailability and antioxidant effect of epigallocatechin gallate administered in purified form versus as green tea extract in healthy individuals. J Nutr Biochem 16: 610–616.
    1. Ho HVT, Sievenpiper JL, Zurbau A, Mejia SB, Jovanovski E, Au‐Yeung F et al. (2016). A systematic review and meta‐analysis of randomized controlled trials of the effect of barley β‐glucan on LDL‐C, non‐HDL‐C and apoB for cardiovascular disease risk reduction. Eur J Clin Nutr . doi:.
    1. Jiao R, Zhang Z, Yu H, Huang Y, Chen ZY (2010). Hypocholesterolemic activity of grape seed proanthocyanidin is mediated by enhancement of bile acid excretion and upregulation of CYP7A1. J Nutr Biochem 21: 1134–1139.
    1. Jiarong L, Yanyun Z, Feixia D, Ziyou Y, Wenjie Z, Jinping F et al. (2015). Meta‐analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol 161: 69–81.
    1. Klimek M, Wang S, Ogunkanmi A (2009). Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. Pharm Therapeut 34: 313–327.
    1. Kris‐Etherton PM, Krummel D, Russell ME, Dreon D, Mackey S, Borchers J et al. (1988). The effect of diet on plasma lipids, lipoproteins, and coronary heart disease. J Am Diet Assoc 88: 1373–1400.
    1. Kroft KD (2016). Dietary flavonoids: antioxidants or not? Arch Biochem Biophys 595: 120–124.
    1. Kuhn DJ, Burns AC, Kazi A, Dou QP (2004). Direct inhibition of the ubiquitin‐proteasome pathway by ester bond‐containing green tea polyphenols is associated with increased expression of sterol regulatory element‐binding protein 2 and LDL receptor. Biochim Biophys Acta 1682: 1–10.
    1. Lachenmeier DW, Monakhova YB, Kuballa T, Loebell‐Behrends S, Maixner S, Kohl‐Himmelseher M et al. (2012). Regulatory evaluation of red yeast rice (Monascus spp) food supplements sold via internet. Dtsch Lebensmitt Rundsch 108: 357–360.
    1. Lee SW, Rho MC, Nam JY, Lim EH, Kwon OE, Kim YH et al. (2004). Guineensine, an Acyl‐CoA: cholesterol acyltransferase inhibitor, from the fruits of Piper longum . Planta Med 70: 678–679.
    1. Leifert WR, Abeywardena MY (2008). Grape see and red wine polyphenol extracts inhibit cellular cholesterol uptake, cell proliferation, and 5‐lipoxigenase activity. Nutr Res 28: 842–850.
    1. Lin CC, Li TC, Lai MM (2005). Went rice in subjects with hyperlipidemia. Eur J Endocrinol 153: 679–686.
    1. Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fonnebo V (2006). Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta‐analysis of randomized controlled trials. Chin Med 1: 4.
    1. Liu CS, Zheng YR, Zhang YF, Long XY (2016). Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia 109: 274–282.
    1. Mannarino MR, Ministrini S, Pirro M (2014). Nutraceuticals for the treatment of hypercholesterolemia. Eur J Intern Med 7: 592–599.
    1. Marazzi M, Cacciotti L, Pelliccia F, Iaia L, Volterrani M, Caminiti G et al. (2011). Long‐term effects of nutraceuticals (berberine, red yeast rice, policosanol) in elderly hypercholesterolemic patients. Adv Ther 28: 1105–1113.
    1. Merriam‐Webster Online Dictionary (2014). Merriam‐Webster Inc., P.O. Box 281, Springfield, MA 01102, United States.
    1. Millán J, Pintó X, Muñoz A, Zuniga M, Rubies‐Prat J, Paillardo LF et al. (2009). Lipoprotein ratios: physiological significance and clinical usefulness in cardiovascular prevention. Vasc Health Risk Manag 5: 757–765.
    1. Mollace V, Sacco I, Janda E, Malara C, Ventrice D, Colica C et al. (2011). Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia 82: 309–316.
    1. Nagasako‐Akazome Y, Kanda T, Ikeda M, Shimasaki H (2005). Serum cholesterol‐lowering effect of apple polyphenols in healthy subjects. J Oleo Sci 54: 143–151.
    1. NCEP (2001). Executive summary of the third report of the national cholesterol education program (ncep), expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285: 2486–2497.
    1. Ong YC, Aziz Z (2016). Systematic review of red yeast rice compared with simvastatin in dyslipidemia. J Clin Pharm Ther 41: 170–179.
    1. Pang J, Zhang Z, Zheng T, Bassig BA, Mao C, Liu X et al. (2016). Green tea consumption and risk of cardiovascular and ischemic related diseases: A meta‐analysis. Int J Cardiol 202: 967–974.
    1. Pascual‐Ahuir A, Vanacloig‐Pedros E, Proft M (2014). Toxicity mechanisms of the food contaminant citrinin: application of a quantitative yeast model. Nutrients 6: 2077–2087.
    1. Pereira MA, O'Reilly E, Augustsson K, Fraser GE, Goldbourt U, Heitmann BL et al. (2004). Dietary fiber and risk of coronary heart disease: a pooled analysis of cohort studies. Arch Intern Med 164: 370–376.
    1. Reiner Z (2014). Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis 24: 1057–1066.
    1. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O et al. (2011). European Association for Cardiovascular Prevention and Rehabilitation. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 32: 1769–1818.
    1. Rocha M, Banuls C, Bellod L, Jover A, Victor VM, Hernandez‐Mijares A (2011). A review on the role of phytosterols: new insights into cardiovascular risk. Curr Pharm Des 17: 4061–4075.
    1. Rouyanne TR, Geleijnse JM, Trautwein EA (2014). LDL‐cholesterol‐lowering effect of plant sterols and stanols across different dose ranges: a meta‐analysis of randomised controlled studies. Br J Nutr 112: 214–219.
    1. Santini A (2014). Nutraceuticals: An Healthy Bet for the Future. J Food Res 3: 1–2.
    1. Santini A, Raiola A, Meca G, Ritieni A (2015). Aflatoxins, ochratoxins, trichotecenes, patulin, fumonisins and beauvericin in finished products for human consumption. J Clin Toxicol 5: 265–277.
    1. Shaghaghi MA, Abumweis SS, Jones PJ (2013). Cholesterol‐lowering efficacy of plant sterols/stanols provided in capsule and tablet formats: results of a systematic review and meta‐analysis. J Acad Nutr Diet 113: 1494–1503.
    1. Sherry Chow HH, Iman AH, Donna RV, Crowell JA, Ranger‐Moore J, Chew WM et al. (2005). Effects of dosing condition on the oral bioavailability of green tea catechins after single‐dose administration of polyphenon e in healthy individuals. Clin Cancer Res 11: 4627–4633.
    1. Smet ED, Mensink RP, Plat J (2012). Effects of plant sterols and stanols on intestinal cholesterol metabolism: Suggested mechanisms from past to present. Mol Nutr Food Res 56: 1058–1072.
    1. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP et al. (2016). The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl. Acids Res. 44: D1054–D1068.
    1. Tenore GC, Campiglia P, Stiuso P, Ritieni A, Novellino E (2013). Nutraceutical potential of polyphenolic fractions from Annurca apple (M. pumila Miller cv Annurca). Food Chem 140: 614–622.
    1. Tenore GC, Calabrese G, Stiuso P, Ritieni A, Giannetti D, Novellino E (2014). Effects of Annurca apple polyphenols on lipid metabolism in HepG2 cell lines: a source of nutraceuticals potentially indicated for metabolic syndrome. Food Res Int 63: 252–257.
    1. Tenore GC, Caruso D, Buonomo G, D'Urso E, D'Avino M, Campiglia P et al. (2016). Annurca (M. pumila Miller cv Annurca) apple as a functional food for the contribution to a healthy balance of plasma cholesterol levels: results of a randomised clinical trial. J Food Sci Agric In press. doi:.
    1. Vinogradova Y, Coupland C, Brindle P, Hippisley‐Cox J (2015). Patients who discontinued statin treatment: a protocol for cohort study using primary care data. BMJ Open 5: e008701. doi:.
    1. Volpe R, Sotis G (2015). Nutraceuticals: definition and epidemiological rationale for their use in clinical practice. High Blood Pres Cardiovasc Prev 22: 199–201.
    1. Weingärtner O, Baber R, Teupser D (2014). Plant sterols in food: no consensus in guidelines. Biochem Biophys Res Commun 446: 811–813.
    1. Yasuda A, Natsume M, Osakabe N, Kawahata K, Koga J (2011). Cacao polyphenols influence the regulation of apolipoprotein in HepG2 and Caco2 cells. J Agric Food Chem 59: 1470–1476.
    1. Yousaf S, Butt MS, Suleria HAR, Iqbal MJ (2014). The role of green tea extract and powder in mitigating metabolic syndromes with special reference to hyperglycemia and hypercholesterolemia. Food Funct 5: 545–556.
    1. Zeisel SH (1999). Regulation of “nutraceuticals”. Science 285: 1853–1855.
    1. Zhu JX, Tang D, Feng L, Zheng ZG, Wang RS, Wu AG et al. (2013). Development of self‐microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride. Drug Dev Ind Pharm 39: 499–506.

Source: PubMed

3
Tilaa