Phytosterols and vascular diseaseSaji John, Alexey V. Sorokin and Paul D. Thompson Phytosterols and stanols are plant derivatives that compete The remarkable reductions in low-density lipoprotein with cholesterol for intestinal absorption and thereby lower cholesterol (LDL-C) levels produced by the hydroxyl- serum cholesterol concentrations. They have been methyl-glutaryl coenzyme-A (HMG CoA) reductase developed as food additives to help lower serum inhibitors or statins have revolutionized the treatment cholesterol but there is concern that these additives could of atherosclerotic cardiovascular disease (ASCVD) inadvertently increase cardiovascular risk. This concern Nevertheless, these agents reduce the incidence of arises from the observation that patients with the rare ASCVD by only approximately 30% warranting a genetic condition phytosterolemia overabsorb phytosterols search for complementary approaches both to reduce and develop premature atherosclerosis. This review LDL-C concentrations and ASCVD risk.
evaluates the relationship between phytosterol and stanolsupplementation and cardiovascular risk.
Plant sterols and their saturated derivatives, stanols, reduce LDL-C by competitively inhibiting intestinal Plant sterol supplementation produces minimal increases in cholesterol absorption and can be used alone or with blood phytosterol concentrations in humans. Recent animal statins and other medications ostensibly to reduce studies suggest that phytosterols reduce atherosclerosis in ASCVD risk. Despite such putatively beneficial effects the Apo-E deficient mouse model. The evidence from in lowering LDL-C concentrations, there are three areas human studies is mixed and does not prove or disprove an of concern regarding their widespread use. First, rare increase in atherosclerotic risk from serum phytosterol individuals with the disease phytosterolemia overabsorb levels. An increase in risk seems unlikely, but additional plant sterols and develop premature ASCVD Second, studies should address this possibility.
phytosterols have been detected in atherosclerotic lesions from individuals with apparently normal choles- Phytosterols are effective in lowering low-density terol absorption Third, some studies suggest that lipoprotein-cholesterol levels, and do not appear to increase elevated serum concentrations of plant sterols are associ- atherosclerotic risk, but additional research on this topic is ated with increased ASCVD disease This review examines the evidence linking phytosterols supplement-ation and ASCVD.
Keywordsatherosclerosis, atherosclerotic cardiovascular disease, cholesterol, coronary artery disease phytosterolemia, The medical literature was systematically searched through to 31 August 2006 using PubMed and Medlineas the search sources and the word combinations phytos- Curr Opin Lipidol 18:35–40. ß 2007 Lippincott Williams & Wilkins.
terols and atherosclerosis, sitosterol and atherosclerosis,phytosterols. Relevant articles were reviewed by the Section of Preventive Cardiology, Division of Cardiology, The Henry Low Heart primary author and included if pertinent to the topic.
Center, Hartford Hospital, Hartford, Connecticut, USA Correspondence to Paul D. Thompson, MD, Cardiology Division, Hartford Hospital,80 Seymour Street, Hartford, CT 06102, USA Tel: +1 860 545 2899; fax: +1 860 545 2882; e-mail: The phytosterols (including sitosterol, campesterol, and Conflict of interest: Dr Thompson owns stock in Merck, Pfizer, and Schering- bressicasterol) and their saturated derivatives, the stanols, Plough, has received research support from Merck, Pfizer, Schering-Plough, are naturally occurring plant derivatives. Stanols are Bristol-Myers Squibb, AstraZeneca, and Kos Pharmaceuticals and has servedas either a paid speaker or consultant for Merck, Pfizer, Schering-Plough, less abundant in nature. The primary sources of phytos- Bristol-Myers Squibb, AstraZeneca, and Kos Pharmaceuticals.
terols are vegetables, nuts, fruits and seeds. Seeds contain Current Opinion in Lipidology 2007, 18:35–40 an average of 120 mg of plant sterols/100 g wet weight,vegetables contain 20 mg/100 g of wet weight and fruit about 15 mg/100 g wet weight. Sitosterol, campesterol and stigmasterol are most abundant in nature comprising 65%, 30%, and 3% of dietary phytosterol intake Phytosterols and cholesterol are structurally similar ß 2007 Lippincott Williams & Wilkins0957-9672 but are metabolized differently. The average western Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
diet approximately contains 200–500 mg of cholesterol, sterols versus the usual level of below 1% Phytos- approximately 200–400 mg of plant sterols and 20–50 mg terolemia patients present at a young age with tendon of plant stanols Humans absorb 55–60% of dietary xanthomas similar to familial hypercholesterolemia and cholesterol and less than 5% of phytosterols clinical symptoms produced by premature atherosclerosisincluding angina, myocardial infarction and sudden death Absorption of cholesterol and phytosterols Non-cardiac abnormalities include abnormal red In the intestine, plant sterols are initially solubilized into cells, hemolysis, thrombocytopenia and abnormal liver a micelle form. These micelles interact with brush border function tests The primary difference between cells and are transferred into enterocytes. Plant sterols are familial hypercholesterolemia and phytosterolemia is esterified within the enterocyte, assembled into chylo- that the latter has normal or slightly elevated choles- microns and secreted into the lymphatics. They are terol levels, but a high ratio of serum plant sterol to excreted via the biliary system. The nonesterified phy- cholesterol. In one of the above-mentioned patients tosterols are transported back into the intestinal lumen by the tendon xanthomas had a plant sterol content of only sterolin (1 and 2) pumps containing the ATP binding 17.5% This raises the possibility that phytosterols cassette (ABC) proteins encoded by the genes ABCG5 facilitate the deposition of other material in extravascular and ABCG8. These are expressed in the mucosal cells and the canalicular membrane, and they resecrete sterols,especially absorbed plant sterols, back into the intestinal lumen and from the liver into bile Defects of either Phytosterolemia is an autosomal recessive disorder of these co-transporters lead to the rare inherited disease with an incidence of one in five million people. Homo- of phytosterolemia. The molecular mechanisms respon- zygosity (but not heterozygosity) for defects in either sible for the transfer into the enterocyte are not fully ABCG5 or ABCG8 genes is implicated. These genetic elucidated. Recently it has been revealed that the defects eliminate the reverse transport of phytosterols Niemann–Pick C1-like 1 (NPC1L1) transporter is most into intestinal lumen, increase phytosterol absorption, likely responsible for the transport of cholesterol and decrease biliary excretion and ultimately lead to phytos- plant sterols from the brush border membrane into the intestinal mucosa. Ezetimibe interferes with NPC1L1,reducing the intestinal uptake of cholesterol and plant The ABCG5 and ABCG8 genes are located on chromo- sterols Stanols are absorbed less than sterols some 2p21 These genes have been mapped in (0–3%) and increasing the length of the side chain of Amish-Mennonite, Finnish, Indian and Japanese families phytosterols increases hydrophobicity and decreases Heterozygotes for functional defects in ABCG5 or absorption Because of their lower intestinal absorp- ABCG8 do not manifest clinical symptoms. They do have tion and preferential biliary excretion, plant sterols com- increased phytosterol absorption, but normal serum prise less than 1% of total circulating sterols in humans levels because of rapid biliary excretion . Unabsorbed sterols undergo transformation byintestinal microflora to produce metabolites such as cor- posterol and corpostanone The standard colori- metric and enzymatic methods used to measure blood The diagnosis of phytosterolemia should be considered cholesterol identify the double bonds between C5 in young patients presenting with tendon xanthomas, and and C6 and 3b-hydroxy bonds respectively. Since evidence of premature atherosclerosis Their total phytosterols also contain these bonds conventional cholesterol concentrations may be slightly elevated, cholesterol measurements do not distinguish between and they may have no family history of hypercholester- cholesterol and phytosterols. To be correctly identified, olemia. Since routine enzymatic and colorimetric assays phytosterol and stanol concentrations must be measured measure phytosterols as cholesterol, GLC or HPLC is by gas liquid chromatography (GLC) or high performance required to distinguish phytosterols from cholesterol Historically the treatment of phytosterolemia included adiet restricted in cholesterol and plant sterols, bile salt binding resins, ileal bypass surgery and plasmapheresis Phytosterolemia is a rare autosomal recessive disorder, but ezetimibe has revolutionized treatment characterized by markedly increased tissue and plasma because it directly impedes sterol absorption sterol concentrations leading to premature ASCVD. Phy- Statins tend to increase phytosterol concentrations tosterolemia was first described by Bhattarcharya and possibly by increasing sterol absorption In phytos- Connor in 1974 in two sisters who presented with xantho- terolemia the activity of HMG CoA reductase is low and matosis, normal cholesterol levels, and, elevated sitos- membrane expression of the hepatocyte LDL receptor terol levels. Their sitosterol levels were 27.1 mg/dl and is increased, so statins are less effective in reducing 17.7 mg/dl, comprising 11% and 16% of their circulating Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Phytosterols and vascular disease John et al.
animals provided with either phytosterol or probucol.
Plant sterols are used to lower the serum cholesterol Compared to the controls, probucol given mice had levels. They decrease the cholesterol absorption of plant accelerated atherosclerosis by threefold. Phytosterol- sterols and were documented to lower serum cholesterol treated animals had half the disease of the controls as early as 1951 by Peterson, who fed chicks with plant These same authors have also used the Apo-E sterols In 1957, Eli Lilly introduced sitosterol as a deficient mouse model to document that phytosterols cholesterol lowering agent called Cytellin. Because of its reduce progression of established atherosclerotic lesions.
poor water solubility and poor bioavailability, it was not Apo-E deficient mice were fed western diets for 14 weeks highly effective or profitable and was taken off the to induce atherosclerosis and subsequently fed them a market. Esterification of plant stanols with fatty acids diet enriched with phytosterols for an additional 25 convert them from a crystalline powder with low lipid weeks. Atherosclerotic lesion progression was reduced solubility into fatty substances that can be incorporated in the plant sterol treated group (28% versus 40%) .
into a variety of foods This property allows them to Again using similar Apo-E deficient mice these investi- be used as additives in fatty foods such as Benecol gators compared the progression of atherosclerosis in (Raisio, Finland; McNeil Nutritionals LLC, Ft. Washing- controls, with groups treated with phytosterol, phytos- ton Pennsylvania, USA) and Take Control (Unilever, terol and cyclosporin, or cyclosporin Atherosclerotic London, UK) margarines, which contain plant stanol lesion size was least in the phytosterol-treated animals and sterol esters, respectively. The reduction of LDL- (0.15 mm2, mean), intermediate in the combination C obtained by phytosterols and stanols in doses of therapy group (0.22 mm2, mean) and greatest (0.41 and 0.7 g/day to 2.5 g/day ranges from 6.7% to 11.3% 0.42 mm2, means) in the control and cyclosporine-treat- This effect is additive to the effect of statins and the ment groups. Similar differences were also observed in addition of 5.1 g/day of phytosterol to statins produces an additional 15% reduction in LDL-C concentrationBoth phytosterols and stanols are well tolerated Results from Plat et al. also suggest that plant sterols and stanols are not atherogenic. These authorsstudied the effect of atorvastatin-induced increases in Phytosterols, atherosclerosis and vascular serum plant sterol and stanol concentrations on the size and severity of atherosclerotic lesions in heterozygous The presence of premature ASCVD in individuals with LDL receptor deficient mice. Atherosclerotic lesion phytosterolemia raises the possibility that even mild development was assessed in controls (fed western diets increases in serum phytosterol concentrations may be alone) compared with five groups fed diets enriched with atherogenic. This has important implications because either atorvastatin; plant sterols; plant stanols; aorvastatin phytosterols are increasingly used as a dietary component and plant sterols; or atorvastatin and plant stanols.
to lower serum cholesterol and they produce small Atorvastatin induced elevations of plant sterols and sta- increase in serum phytosterol levels, about 0.6–2 mg/dl nols did not accelerate atherogenesis (In a com- The possibility that phytosterols increase ASCVD panion study, atherosclerosis was induced in the mice risk has been examined using animal models, tissue before 12 weeks of treatment with sterol esters, stanols esters or atorvastatin. Compared to controls, animals treated with the sterols and stanols showed regressionof the atherosclerotic lesions by 66 and 64%, respectively Moghadasian et al. compared a standard westernchow diet with or without phytosterols derived from tall oil (phytosterol mixture) in Apo-E deficient mice. They There are at least seven studies that have examined the found reduced atherosclerotic lesions in the phytosterol possibility that phytosterols may contribute to ASCVD fed mice. In the same Apo-E deficient mouse model, risk. Glueck et al. were the first to suggest that these investigators compared control fed animals with elevated phytosterols may be a risk factor for coronary Table 1 Morphometric features of atherosclerotic lesions in apo-E knockout mice treated with cyclosporine or phytosterols or both à P < 0.05 as compared to either controls or cyclosporine-treated group.
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Figure 1 Lesion areas in female heterozygous LDL receptor artery disease (CAD). These authors measured serum cholesterol as well as phytosterols by GLC and thin layerchromatography in 595 patients with hypercholesterol-emia. Elevated phytosterols levels were associated with a family history of CAD suggesting that slightly elevatedphytosterols were a heritable risk factor.
Sutherland and Williams in 1998 examined theassociation of plant sterol levels and angiographicallydetermined CAD in 44 patients with similar cholesterol levels. The severity of CAD was inversely related to the ratio of plasma lathosterol to sitosterol. Since lathosterol isan indicator of cholesterol production and sitosterol an indicator of sterol absorption, the inverse relationship suggests that high plant sterol absorption is related to increased CAD severity. Increased plant sterol absorp- tion, however, may also be an indicator of increased cholesterol absorption; hence increased phytosterolabsorption is often secondary to inhibition of cholesterol Mice were fed plants stanols (1% w/w), plant sterols (1% w/w),atorvastatin (0.0025% w/w), plant stanols (1% w/w) plus atorva- synthesis that in turn stimulates cholesterol absorption.
statin (0.0025% w/w) or plant sterols (1% w/w) plus atorvastatin(0.0025% w/w) for 35 weeks. Plant sterols and stanols were fed as Rajaratnam et al. measured serum squalene, des- fatty acid esters. ÃP < 0.001 versus control; #P < 0.05 versus ator-vastatin. Reproduced with permission mosterol and lathosterol levels (as indicators of choles-terol synthesis), and serum cholestanol, campesterol andsitosterol levels (as indicators of cholesterol absorption) in48 postmenopausal women with angiographically verifiedCAD and in 61 controls. The CAD patients had a higherratio of plant sterols to cholesterol and decreased ratio of Figure 2 Lesion areas in female heterozygous LDL receptordeficient mice lathosterol to cholesterol suggesting that low cholesterolsynthesis may cause increased plant sterol absorption andmay increase CAD risk, although as stated above this may have also indicated increased absorption of cholesterol.
Unfortunately, there was no attempt to assess occult Sudhop et al. compared phytosterol levels in 53 patients undergoing coronary artery bypass graft surgery. Phytos-terol levels were increased (campesterol 0.50 mmol/lversus 0.38 mmol/l, P ¼ 0.001; sitosterol 0.40 mmol/l versus0.11 mmol/l, P ¼ 0.004) among patients with a family history of CAD suggesting that genetically increasedphytosterol absorption may increase CAD risk.
Miettinen et al. measured total cholesterol, esterified cholesterol, and phytosterol levels in serum and arterialtissue obtained from patients undergoing carotid endar- terectomy (n ¼ 25). Those patients with a higher ratio of absorption of plant sterols to cholesterol had a corre- sponding higher ratio of phytosterols to cholesterol in atherosclerotic arterial tissues, suggesting that increasedphytosterol absorption does contribute to development ofatherosclerotic lesions.
Mice were fed with Western type control diet for 33 weeks (atherogenicperiod) followed by a 12-weeks period (regression period) in whichanimals were fed with plant stanols (2% w/w) sterols (2% w/w) or The Prospective Cardiovascular Munster (PROCAM) atorvstatin (0.005% w/w). ÃP ¼ 0.016 versus controls and #P ¼ 0.026 study is a nested, case –control, 10-year follow-up study versus controls. Reproduced with permission of a random sample of the Munster population. Sitosterol Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Phytosterols and vascular disease John et al.
levels in men with a CAD event (n ¼ 159) were compared reduction in this population It remains possible that with controls without CAD (n ¼ 318). Patients with individuals with polymorphisms in the ABCG5 and sitosterol levels of 5.25 mmol/l had a 1.8-fold increase ABCG8 genes that affect phytosterol absorption are at in CAD risk when compared to controls whose average altered risk because of their ability to overabsorb phy- sitosterol level was 4.27 Æ 2.38 mmol/l (P < 0.05). Among high risk subjects, defined as having an estimated globalCAD risk of greater than 20% in 10 years, serum sitosterol Additional studies on this topic are clearly warranted.
levels were higher (P ¼ 0.032) and CAD risk increased These should examine whether increased blood phytos- terol concentrations increase ASCVD risk and whetherreductions in LDL-C levels by agents such as ezetimibe The Dallas Heart Study measured plasma cholesterol, produce greater than expected reductions in ASCVD risk sitosterol and campesterol levels in 3254 subjects, aged for the reduction in cholesterol. At the present time, there 30–65 years obtained from a probability based sample of is not sufficient evidence to advise against phytosterol Dallas County, Texas. They compared the mean levels of supplementation to reduce LDL-C levels. Promotion for plant sterols in individuals with a plasma level of cho- the use of plant sterols for LDL-C lowering is increasing, lesterol of more than 240 mg/dl, and a positive family but prudence dictates that the dose of phytosterols history of CAD to those with no family history of should not exceed 2 g/day. An additional concern of CAD. No significant differences in plasma sitosterol uncertain significance is the interference with the absorp- (0.16 Æ 0.003 mg/dl versus 0.16 Æ 0.004 mg/dl) or campes- terol (0.26 Æ 0.004 mg/dl versus 0.27 Æ 0.005 mg/dl) werefound between the two groups. These results suggest that phytosterol levels do not contribute to familial coronary Papers of particular interest, published within the annual period of review, have This study also compared plasma cholesterol, sitosterol, Additional references related to this topic can also be found in the Current and, campesterol levels in 2542 subjects who underwent World Literature section in this issue (pp. 99–100).
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