The effect of nutritional supplements on serum high-density lipoprotein cholesterol and apolipoprotein A-I.

Am J Cardiovasc Drugs DOI 10.1007/s40256-014-0068-1

REVIEW ARTICLE

The Effect of Nutritional Supplements on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I Arshag D. Mooradian • Michael J. Haas

Ó Springer International Publishing Switzerland 2014

Abstract One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). Diet has an important role in modulating HDL cholesterol level. The widespread use of nutritional supplements may also alter the biology of HDL. In this review, we discuss the effect of select nutritional supplements on serum HDL cholesterol and apo A-I levels. Some nutritional supplements, such as phytosterols, soy proteins, and black seed extracts, may increase HDL cholesterol levels, while others such as cholic acid and high doses of commonly used antioxidant vitamins may downregulate HDL cholesterol levels and reduce its cardioprotection. Multiple mechanisms are involved in the regulation of HDL levels, so changes in production and clearance of HDL may have different clinical implications. The clinical relevance of the changes in HDL and apo A-I caused by nutrient supplementation needs to be tested in controlled clinical trials.

1 Introduction Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world. The Western diet has been suspected to be an important contributor to the increased prevalence of CVD. Nutritional

A. D. Mooradian (&) M. J. Haas Department of Medicine, University of Florida College of Medicine, 653-1 West 8th Street, 4th Floor, LRC, Jacksonville, FL 32209, USA e-mail: [email protected]

factors modulate the progression of vascular disease through multiple mechanisms, including promotion of obesity, hypertension, and unfavorable changes in plasma lipid profile. The latter typically includes an increase in low-density lipoprotein (LDL) cholesterol (LDLc), increased triglycerides, and reduced high-density lipoprotein (HDL) cholesterol (HDLc). Epidemiological studies, as well as studies in animal models, of atherosclerosis support the cardioprotective role of HDL [1, 2]. Thus, dietary interventions that result in increased HDLc levels may have favorable effects on an individual’s health [3, 4]. However, currently recommended heart-healthy diets focus on reducing dietary intake of saturated fat and cholesterol, which often results in decreased plasma LDLc and HDLc [5, 6]. Whether nutritional supplements, when combined with a low-fat diet, are able to optimize the plasma lipid changes by maintaining or enhancing HDLc levels remains unknown. Nutritional supplement use is widespread. According to a report published in 1997, over one-third of North American adults use herbal medicinal products, at an annual cost of $US13.7 billion [7]. However, there is a paucity of evidence as to the healthcare benefits of nutritional supplements. Most studies are either small or observational non-randomized studies. In this communication, the effect of select nutritional supplements on HDLc, HDL and its main protein component apolipoprotein A-I (apo A-I) levels is reviewed.

2 Biological Functions of High-Density Lipoprotein (HDL) and its Apolipoproteins (apo) The group of lipoproteins referred to as HDL vary in size, density, and protein and lipid composition. The HDL2,

A. D. Mooradian, M. J. Haas

HDL3, and pre b-HDL represent the largest most buoyant to smaller and denser HDL particles, respectively [8]. As for categorization based on apolipoprotein composition, the two large groups of HDL include the LpA-I (that contains mostly apo A-I) and the LpA-I:AII that contains apo A-II in addition to the apo A-I, the main protein component. Additional minor apolipoproteins that contribute to the structure and function of HDL include apo Cs (i.e. C-I, C-II, and C-III) and apo E [8]. The cardioprotective advantage of HDL2 relative to HDL3 is controversial [8– 10]. There are multiple mechanisms for the proposed atheroprotective effects of HDL and apo A-I. The principal mechanism is through reverse cholesterol transport [8–10]. Cholesterol that is exported from target tissues mostly through the action of adenosine triphosphate (ATP)-binding cassette transporter 1(ABCA1) is taken up by the nascent HDL that continues to grow into HDL3 and HDL2 by accepting additional cholesterol while transporting it to the liver. The apo A-I is released as cholesterol ester and is taken up in the liver through scavenger receptor type B, class 1 (SRB1). Other atheroprotective mechanisms include antioxidant and anti-inflammatory activity of HDL and its association with two enzymes, namely paraoxonase and the plateletactivating factor acetylhydrolase. Antithrombotic and fibrinolytic activities further enhance the atheroprotective effects of HDL. Whether HDL is cardioprotective or is simply a marker of CVD remains controversial [11]. Epidemiological studies have shown that low HDLc is an independent predictor of coronary heart disease risk. In some interventional trials with statins, the deleterious effects of low HDLc persisted even after reducing the LDLc to 70 mg/dL [12]. However, some of the genetic conditions associated with high plasma HDLc do not lower the risk of myocardial infarction [13]. In addition, in recent interventional trials where niacin or cholesterol ester transfer protein (CETP) inhibitors were used in patients receiving intensive statin therapy, there were no favorable effects on CVD endpoints despite significantly increasing HDLc [14–16]. It is possible that currently available drugs that raise HDLc mostly through inhibition of turnover of HDLc are not effective in reducing clinical events. Future interventions, whether pharmaceutical or nutritional, that target the de novo synthesis of apo A-I and HDL may be more effective in reducing cardiovascular events [11].

HDLc is summarized in Table 1. In general, HDLc and apo A-I levels increase with consumption of diets enriched with saturated fat. This effect has been mostly attributed to a decrease in the clearance of HDLc and possibly to other translational and post-translational changes in apo A-I, ABCA1, ABCG1, CETP, and SRB1 [3, 17, 18]. However, diets enriched in saturated fatty acids, unlike diets enriched in unsaturated fatty acids, are also associated with increased apo A-II levels [6]. This effect is gender specific [19, 20], as the National Cholesterol Education Program (NCEP) Step II diet reduces HDLc and apo A-I levels more in women than in men [19]. In the context of a low-fat, high-carbohydrate diet, the lowering of LDLc and HDLc occur equally whether the diet is enriched with polyunsaturated fatty acids (PUFA) or monounsaturated fatty acids (MUFA). However, the MUFA-rich diet does not lower apo A-I concentrations as much as does the PUFA-rich diet [21, 22]. Relative to saturated fatty acids, trans-fatty acids/ hydrogenated fat-enriched diets are either equivalent or more potent in increasing LDLc levels, and, unlike saturated fatty acids, they may decrease HDLc levels [23–27]. The reduction in apo A-I gene promoter activity in the presence of trans-fatty acids demonstrated in cell cultures is consistent with the literature on the effect of dietary trans-fatty acids on lowering HDL levels [26]. Compared with oleic acid, medium-chain fatty acids may raise LDLc concentrations slightly and affect the apo A-I to apo B ratio unfavorably. However, their overall effects on plasma lipids and lipoproteins are modest [28]. The increase in HDLc attributed to increased dietary fat could be secondary to reduced carbohydrate content of the diet. Dextrose downregulates apo A-I gene expression, while insulin upregulates it [29]. A fructose-enriched diet may increase cardiovascular risk [30]. Although a diet enriched with saturated fats increases HDLc, it also raises LDLc, resulting in a net detrimental effect on cardiovascular risk. It is noteworthy that genetic factors influence the response of plasma lipids to dietary interventions [31]. The current evidence suggests that a diet enriched in monounsaturated fat and to a lesser extent PUFA with some carbohydrate restriction (i.e. not to exceed 40 % of calories) would have the most favorable effects on HDLc and apo A-I levels.

3 Dietary Modulation of HDL and apo A-I

In addition to the role of macronutrients in modulating HDLc levels, micronutrients as well as other nutritional supplements can have clinically significant effects on plasma lipids.

Dietary composition is an important determinant of the plasma HDLc level. The effect of various nutrients on

4 Effect of Nutritional Supplements on HDL Cholesterol and apo A-I

Nutritional Supplements and HDL Table 1 The putative mechanism of the effects of macronutrients and select nutritional supplements on high-density lipoprotein cholesterol and apolipoprotein A-I levels Nutrient/supplement

Clinical effects

Predominant/known mechanism

: HDLc and apo A-II

; plasma clearance

I. Dietary fat Saturated fat

NC or : apo A-I

; apo A-I gene expression

PUFA

: HDLc and apo A-I

; plasma clearance

MUFA

: HDLc and apo A-I

; plasma clearance

Prevents lowering of apo A-I in CHO-enriched diets Trans-FA

; HDLc

; apo A-I gene promoter activity

MCFA

; HDLc modestly

Unknown

Cholesterol

NC in HDLc or apo A-I

–

II. CHO Digestible complex CHO

; HDLc and apo-A-I

: plasma clearance ; apo A-I gene expression

Glucose

; HDLc and apo -A-I


Fructose

; HDLc and apo -A-I

Insulin resistance

III. Protein

No effect

–

IV. Alcohol

: HDLc and apo A-I

: apo A-I gene expression

1. Soy proteins 2. Sterols/stanols

: HDLc and apo A-I ; LDLc

: apo A-I gene expression ; cholesterol absorption

3. Glucosamine

No significant effect

Stabilise apo A-I mRNA in cell cultures

4. Fish oil/omega-3 FAs

No significant effect on HDLc; ; TGs

May ; apo A-I mRNA

5. Bile acids

May ; HDLc


6. Black seed oil

NC in HDLc

: apo A-I production in cell cultures

V. Supplements

: HDLc in diabetics

; LDLc 7. Red yeast

Mild : HDLc

Similar to statin effects

; LDLc 8. Vitamins A, C, E, D

NC or ; HDLc

High doses or deficiency ; apo A-I gene expression

VI. Minerals Zinc

NC, : or ;

High doses or deficiency ; apo A-I gene expression

Copper

: HDLc in deficiency

: apo A-I synthesis

Chromium

NC or :

Insulinomimetic; high doses ; apo A-I gene expression in cell cultures

Vanadium/salts

NC or :

Insulinomimetic; high doses ; apo A-I gene expression in cell cultures

VII. Non-vitamin antioxidants Resveratrol Quercetin

: HDLc No effect

: apo A-I gene expression : apo A-I gene expression

Anthocyanin

: HDLc

Inhibit CETP activity, increase reverse cholesterol transport

apo apolipoprotein, CETP cholesterol ester transfer protein, CHO carbohydrates, FA fatty acid, HDLc high-density lipoprotein cholesterol, MCFA medium-chain fatty acid, mRNA messenger RNA, MUFA monounsaturated fatty acid, NC no change, PUFA polyunsaturated fatty acid, TG triglyceride, : indicates increase, ; indicates decrease

CHO carbohydrates, db double-blind, co crossover, HDLc high-density lipoprotein cholesterol, LDLc low-density lipoprotein cholesterol, NS not significant, PL placebo, ran randomized, TC total cholesterol, : indicates increased, ; indicates decreased

Genistein improved lipids and insulin resistance : HDLc from 46.4 to 56.8 mg/dL and ; LDLc from 108.8 to 78.7 mg/dL ran, db Squadrito et al. [39]

120 postmenopausal women with metabolic syndrome

Genistein 54 mg daily (n = 60) or PL (n = 60) for 1 year after 4-week run-in period

Soy protein did not have significant effects on lipids Significant ; in TC (19 mg/dL) and LDLc (11 mg/dL) during run-in period. No further ; in either group ran, db Ma et al. [38]

159 adults

Soy protein (n = 81) vs. milk protein (n = 78) for 5 weeks after 3 week runin period

No significant effects of isoflavone on lipids vs. PL TC and LDLc ; in both groups. HDLc : by 4.3 mg/dL in isoflavone group and by 7.9 mg/dL in PL (p NS) ran, db, co Rios et al. [37]

47 Brazilian postmenopausal women

40 mg isoflavone (n = 25) or 40 mg casein (PL) for 6 months

Soy protein improves lipid profile modestly. No significant change in HDLc Soy proteins vs. CHO ; total cholesterol by 3.97 mg/dL. Versus milk protein, soy increased HDLc by 1.54 mg/dL Ran, db, 3-phase co Wofford et al. [36]

352 US adults with serum cholesterol [240 mg/dL

40 g/day soy protein vs. milk protein vs. complex CHO in random order for 8 weeks with 3-week washout in between phases

Conclusions Changes in lipids Intervention Subjects Design References

Table 2 The effects of soy proteins and isoflavones on lipid profile observed in select clinical trials


4.1 Soy Proteins Soy protein is a commonly consumed nutritional supplement that may have metabolic and hormonal effects. Specific soy components including isoflavones have structural similarities with estrogen and are known to increase HDLc and reduce LDLc levels [32–34]. Indeed, in a hepatoma cell line HepG2, both genistein and daidzein increased apo A-I secretion in a dose-dependent fashion [33]. The effect of genistein on apo A-I secretion was similar to that observed with 17-beta-estradiol [34]. Estrogen promotes the interaction between hepatocyte nuclear factor (HNF)3b and the orphan nuclear receptor HNF-4 on the apo A-I promoter, leading to the release of the estradiol-responsive transcriptional co-repressor, receptor-interacting protein 140, thereby increasing apo A-I gene transcription [35] Table 2 summarizes some of the larger trials with soy protein supplementation. In a randomized controlled study, supplementation with soy protein, but not milk protein, improved the lipid profile among healthy individuals [36]. Additional studies with supplementation of soy proteins had less favorable outcomes on lipid profiles. In a doubleblind randomized trial of 47 postmenopausal Brazilian women, soy isoflavone supplementation had no significant independent effects on lipid profiles [37]. In another randomized controlled trial of 159 subjects, the effect of 5 weeks of soy protein supplementation was not significantly different from that of milk protein in terms of any lipid parameter measured [38]. The source of soy protein and the differences in quantities consumed may explain some of the discrepancy in the literature (Table 2). In a randomized clinical trial of postmenopausal women with metabolic syndrome, treatment with genistein for 1 year (54 mg/day) caused a significant decrease in fasting insulin and glucose levels, as well as decreases in total cholesterol, LDLc, and triglycerides relative to the placebo group. There was also an increase in HDLc and adiponectin levels, as well as decreases in systolic and diastolic blood pressure [39]. These findings suggest that 1 year of treatment with genistein improves several risk factors associated with diabetes and CVD in postmenopausal women with metabolic syndrome. Whether or not these findings can be applied to other patient populations needs to be assessed. A commonly used phytoestrogens-containing nutritional supplement is black cohosh (Cimicifuga racemosa). This plant is also known as black snakeroot, bugbane, bugwort, rattleroot, or rattelwood [40]. The precise mechanism of action of black cohosh is not known; however, it may have selective estrogenic effects on at least some tissues [41]. The effects of black cohosh on plasma lipids are complex and in rats it increases LDLc and decreases triglyceride levels, which is in contrast to the effects of estrogen [42].

The reader is also referred to other reviews and meta-analyses on this topic [50, 57–60]

apo apolipoprotein, db double-blind, HDLc high-density lipoprotein cholesterol, LDLc low-density lipoprotein cholesterol, NC no change, pc placebo-controlled, PL placebo, ran randomized, TC total cholesterol, TG triglyceride, tid three times daily, : indicates increased, ; indicates decreased

Guggulipids may increase LDLc and caused skin hypersensitivity reactions LDLc : by 9–19 % in guggullipid groups. NC in HDLc or TG Guggulipid (containing 2.5 % guggulsterone) 2,000 mg tid (n = 34) vs. 1,000 mg tid (n = 33) vs. PL (n = 36) for 8 weeks ran, db, pc Szapary et al. [56]

103 subjects with hypercholesterolemia

NC in HDLc

Soyprotein and phytosterolcontaining proprietary product improved lipid risk factors Significant improvement in LDLc (132.3 vs. 172.4 mg/dL)

Phytochemical-enhanced diet (n = 12) vs. mediterranean diet (control; n = 12) for 12 weeks ran, pc Lerman et al. [54]

24 adults with metabolic syndrome

Policosanol did not alter serum lipid profile No significant changes in lipid parameters Policosanol 20 mg/day (n = 20) or PL (n = 20) for 8 weeks ran, pc Dulin et al. [53]

40 subjects with hypercholesterolemia

Phytosterols improved lipid risk factors but did not alter HDLc TC ; 15.9 %. LDLc ; by 20.3 %. TG ; by 19.1 %, NC in HDLc or apo A-I Phytosterol 4 g/day in yoghurt drink (n = 53) or yoghurt beverage control (n = 55) for 2 months ran, pc Sialvera et al. [52]

108 adults with metabolic syndrome

Intervention Subjects Design References

Table 3 The effect of phytosterols on lipid profile in select clinical trials

Changes in lipids

Conclusions

Nutritional Supplements and HDL

However, in humans, black cohosh-containing therapies had no demonstrable effects on lipids, glucose, insulin, or fibrinogen [43]. Overall, it appears that dietary supplementation of soy proteins and other phytoestrogens-containing supplements have a modest favorable effect on HDLc and apo A-I levels, body composition, and metabolic profile (Table 2). 4.2 Phytosterols/Stanols The mechanism of action of phytosterols is complex. An important biologic effect of phytosterols is inhibition of intestinal absorption of cholesterol by 26–36 %. Phytosterols reduce cholesterol absorption by inhibiting 27-hydroxycholesterol generation, liver-X-receptor a activation, and expression of the basolateral sterol exporter ABCA1 in Caco2 enterocytes in culture [44]. Guggulsterone, a plant sterol found in the guggul plant Commiphora mukul, is a farnesoid X receptor (FXR) antagonist that elevates plasma HDLc levels in mice [45]. This is not surprising as FXR is known to modulate apo A-I gene expression [46]. Other mechanisms of action of phytosterols include their anti-inflammatory effects, reduction in oxidative stress, favorable changes in coagulation parameters, and beneficial changes in platelet and endothelial function [47]. Epidemiological studies correlating plasma phytosterol concentration with CVD risk have not provided conclusive results. Some studies have found that plasma concentrations of phytosterols correlate with clinically detectable coronary heart disease [48, 49]. Yet most observational studies have shown that consumption of phytosterols is associated with overall decrease of CVD risk with favorable changes in lipid profile, most notably a decrease of 5–15 % in LDLc [50]. Overall, greater phytosterol consumption from natural diets is associated with lower serum total, LDLc, and non-HDLc levels [51]. Some of the seminal studies with phytosterol supplementation are summarized in Table 3. In a randomized placebo-controlled study of 108 patients with metabolic syndrome, phytosterol supplementation (2-plant sterolenriched yoghurt mini drinks that provided 4 g of phytosterols per day) for 2 months decreased plasma small and dense LDL levels but had no effect on HDLc, apo A-I, glucose, C-reactive protein, fibrinogen levels, or blood pressure [52]. Policosanol is one of the over-the-counter supplements used to treat elevated cholesterol. However, recent studies have found that policosanol is ineffective in the treatment of hypercholesterolemia [53]. In a randomized trial of a proprietary nutraceutical supplement containing soy protein, phytosterols, hops rho iso-alpha acids, and Acacia nilotica proanthocyanidins,


Lerman et al. [54] found that, at 12 weeks, the phytochemical-enhanced diet arm exhibited greater improvement in total cholesterol, LDLc, non-HDLc, cholesterol/ HDLc, triglyceride/HDLc, apo B, apo B/apo A-I, homocysteine, total LDL particle number, and large HDL particle number. Guggulsterone isolated from the resin of the guggul tree has been used in Southeast Asia to treat various diseases, including hypercholesterolemia. The efficacy of this compound has not been consistently observed in clinical trials [55], and, in a randomized placebo-controlled study of hypercholesterolemic subjects, guggulsterone unexpectedly elevated plasma LDLc levels [56] (Table 3). Meta-analyses of randomized controlled interventional trials in individuals with non-familial hypercholesterolemia found that foods containing plant sterols/stanols were able to reduce LDLc by a mean of 6.7 % at doses of 0.7–1.1 g/ day and by as much as 11.3 % at doses of C2.5 g/day [50, 57, 58]. There is no statistically or clinically significant difference between plant sterols and plant stanols in their abilities to modify total cholesterol, LDLc, HDLc, or triglycerides [59]. A similar favorable effect of phytosterols on lipid profile is seen in people with type 2 diabetes where placebo-controlled trials have documented that plant sterols/stanols significantly reduce total cholesterol and LDLc, with a trend towards improvement in HDLc [60]. In general, 2 g/day of stanols or sterols reduce LDLc by 10 % and higher intakes add little additional benefit. Foods low in saturated fat and cholesterol and high in stanols or sterols can reduce LDLc by 20 %, and adding sterols or stanols to statin medication is more effective than doubling the statin dose [50, 57]. In those with higher baseline serum concentrations of total and LDL cholesterol, stanols result in larger absolute decreases in cholesterol concentrations [61]. The HDLc concentrations increase in subjects with low baseline concentrations and decrease in those with high baseline concentrations. Thus, people with an unfavorable serum lipid and lipoprotein profile benefit even more with plant stanols than people with a more favorable profile [61]. It is noteworthy that phytosterols encompasse a group of chemicals that may have individual and unique properties and may alter the lipid profile in a distinctive manner. In addition, sterol-enriched foods increase plasma sterol levels, which may pose a theoretical risk as the incidence of CVD is markedly increased in patients with homozygous phytosterolemia [48, 49]. Similarly, there is some controversy as to the effect of plant stanols or sterols on colon carcinogenesis [57]. The preponderance of current evidence supports the clinical utility of sterols and stanols for lowering LDLc levels in individuals at increased risk for coronary heart disease. However, the effect of phytosterol on HDLc is negligible. Long-term randomized placebo-

controlled studies are needed to clarify the effects of supplementation with phytosterols on CVD risk and progression of atherosclerosis. 4.3 Glucosamine Glucosamine is a popular nutritional supplement used for the treatment of osteoarthritis. Since intracellular glucosamine level increases in periods of hyperglycemia, and glucosamine is a potential mediator of insulin resistance [62, 63], it is possible that glucosamine supplementation may alter apo A-I and HDL production. In hepatocytesderived cell cultures, glucosamine unexpectedly increased the amount of apo A-I protein secreted into the culture media [64]. The increase in apo A-I occurs primarily through apo A-I messenger RNA (mRNA) stabilization [64]. However, in a small randomized double-blind study, consumption of 500 mg glucosamine three times daily for 2 weeks did not significantly increase HDLc or apo A-I levels [65]. Future studies should evaluate the effect of higher doses or sustained release glucosamine preparations on HDLc levels. 4.4 Fish Oil and Omega-3 Fatty Acids The precise mechanism of the effect of omega-3 fatty acids on lipids and specifically on HDLc is not known. In primary culture of hepatocytes, addition of the n-3 polys such as docosahexaenoic acid and eicosapentaenoic acid (EPA) decreases apo A-I mRNA in a dose-dependent manner, whereas apo A-II mRNA does not change significantly [66]. In rats, a significant decrease in liver apo A-I and apo A-II mRNA levels was observed after fish oil feeding [66]. There is no evidence that similar changes occur in humans. Fish oil consumption (4 g/day) may alter HDL metabolism in vivo. Some of the clinical studies on the effect of omega-3 fatty acids on apo A-I and HDLc are summarized in Table 4. In one study of the kinetics of HDL, fish oils (4 g/day) decreased the fractional catabolic rate of HDL apo A-I and HDL apo A-II. This was coupled with a significant decrease in the corresponding production rates, accounting for a lack of treatment effect on plasma concentrations of apo A-I and apo A-II [67]. In patients with type 2 diabetes, treatment with dietary fish oil reduced plasma triglyceride levels, but plasma cholesterol level and apo A-I and HDL did not change markedly [68]. However, apo A-I fractional catabolic rate and absolute production rate were significantly decreased after treatment with fish oil [68] (Table 4). In a small study (n = 90) of women with rheumatoid arthritis, serum levels of HDLc (p B 0.018), apo A-I (p B 0.165), aryl esterase (p B 0.026), and paraoxonase-1 (p B 0.049) activity increased with 1 g of fish oil pearl

Design

ran, pc, 292 factorial intervention

ol kinetic. Subjects are their own control

ran, pc

ran,db, pc

ol, not ran

ran, db, pc, 292 factorial trial in four parallel groups

ran, db, PL

References

Chan et al. [67]

Frenais et al. [68]

Ghorbanihaghjo et al. [69]

Maki et al. [70]

Madden et al. [71]

Micallef et al. [72]

Harper et al. [73]

56 participants

60 hyperlipidemic individuals

111 healthy, middle-aged, Caucasian men

57 adults with fasting HDLc B44 (men) and B54 mg/dL (women), but C35 mg/dL

90 women with RA

Five type 2 diabetic pts before and 2 months after tx with fish oil

48 obese men with dyslipidemia

Subjects

Effect of maxEPAÒ on kinetics of apo A-I in type 2 diabetes is probably linked to changes in plasma TG level

NC in cholesterol level. TG ; (155.4 ± 67.9 vs. 202.6 ± 32.2 mg/dL, p = 0.06). NC in plasma apo A-I and HDLc. HDL-apo AI fractional catabolic rate and absolute production rate were significantly ; (p \ 0.05)

3 g/day of ALA from flaxseed oil in capsules (n = 31) or olive oil containing PL capsules (n = 25) for 26 weeks

ALA did not affect TG, LDL, HDL, or IDL particle size

ALA does not ; CVD risk by altering lipoprotein particle size or plasma lipoprotein concentrations

Combined supplementation with PS and (n-3) PUFA has both synergistic and complementary lipid-lowering effects

Combination of PS and PUFA ; TC by 13.3 % (p = 0.001) and LDLc by 12.5 % (p = 0.002). HDLc : by PUFA (7.1 %; p = 0.01) alone and in combination with PS (8.6 %; p = 0.04) and TG was lowered by PUFA (22.3 %; p = 0.004) alone and in combination with PS (25.9 %; p = 0.005). PS alone had no effect on HDLc or TG

Sunola oil or 1.4 g/day (n-3) long-chain PUFA capsules with or without 2 g PS/ day for 3 weeks

TG-lowering effects may be via stimulation of CD36 activity in extra-hepatic tissue in individuals with the GG variants of these SNP

TG ; from 1.48 mol/L to 0.11 mmol/L, and HDLc : from 5.92 to 0.15 mmol/L and from 1.27 to 0.04 mmol/L. Significant falls in TG only occurred in individuals with the GG variant of the 25444, 30294, -31118, or -33137 SNP

6 g MaxEPAÒ daily for 12 weeks

Supplementation with 1.52 g/day of DHA in men and women with below-average HDLc raised the LDLc level, but had favorable effects on TG and the TG/HDLc ratio

DHA group showed significant changes (-43 vs. -14 [controls] mg/dL, p = 0.015 in TG, TC [12 vs. 3 mg/dL; p = 0.02], and LDLc [17 vs. 3 mg/dL; p = 0.001] and in the TG to HDLc ratio [-1.33 vs. -0.50, p = 0.010])

Fish oil could : serum HDLc in women with RA

Fish oils, but not ATO, influenced HDL metabolism chiefly by ; both the catabolism and production of HDL apo A-I

Fish oils and ATO ; plasma TG and increased HDLc (p \ 0.05). Fish oils ; the fractional catabolic rate of HDL apo A-I and HDL apo A-II with significant ; in the corresponding production rates (p \ 0.02), accounting for a lack of effect on apo A-I and apo A-II levels

HDLc (p = 0.018), Apo-AI (p = 0.165), arylesterase (p = 0.026), and paraoxonase-1 (p = 0.049) :. Malondialdehyde levels ; with fish oil supplements (p = 0.077)

Conclusions

Changes in lipids

1.52 g/day DHA or olive oil (control) for 6 weeks

Fish oil pearl (1 g) daily or PL for 3 months

Six capsules n-3-FAs/day with meals for 8 weeks (maxEPAÒ). Each capsule contained 1,000 mg methyl ester FAs, providing 180 mg EPA, 120 mg DHA and 1.75 mg alpha-TAC

Fish oils (4 g/day) with and without and ATO (40 mg/day) on the kinetics of HDL apo A-I and HDL apo A-II

Intervention

Table 4 The effect of fish oil supplements on lipid profile and cardiovascular outcomes in interventional trials


ran, db, pc

ran, db, pc

ran, db, pc

Two ran, db, pc, pg

ran, db, pc

ran, db, pc

ran, pc, db

ran, db, pc

ran, db, pc

Lambert et al. [74]

Kaul et al. [75]

Sanders et al. [77]

Glaxo Smith Kline data on file [78]

Harris et al. [79]

Durrington et al. [80]

Davidson et al. [81]

Bays et al. [82] MARINE Trial

Ballantyne et al. [83]

ANCHOR study

Design

References

Table 4 continued

702 high-risk statin-treated pts with TG levels (C200 and \500 mg/dL) despite LDLc control (C40 and \100 mg/ dL)

229 diet-stable pts with fasting TG C500 mg/dL and B2,000 mg/dL (with or without background of statin therapy)

254 pts on statin therapy for 8 weeks or more and had fasting TG levels C200 and \500 mg/dL and LDLc levels B10 % above their goal

59 pts with CHD, receiving SIM 10–40 mg daily with serum TG [2.3 mmol/L

42 pts with TG concentrations of 500–2,000 mg/dL

84 adult pts on diet regimen with BL TG levels of 500–2,000 mg/dL

20 male pts with primary hypertriglyceridemia

86 healthy volunteers

62 non-obese subjects (25 men, 37 women)

Subjects

TG ; by 45 %

Four 1-g capsules of LovazaÒ (omega-3acid ethyl esters) or PL daily for 6 weeks (one study) or 16 weeks (second study)

VaseptaÒ (eicosapentaenoic acid ethyl ester) 4 g/day, 2 g/day, or PL for 12 weeks

TG level ; by 33.1 % (n = 76, p \ 0.0001) in 4 g/day group and by 19.7 % (n = 73, p = 0.0051) in 2 g/day

VaseptaÒ (eicosapentaenoic acid ethyl ester) 4 g/day, 2 g/day, or PL for 12 weeks

LDLc ; by 6.2 % in 4 g/day (p = 0.0067) and HDLc was reduced by 4.5 % (p \ 0.01)

TG level ; by 21.5 % (p \ 0.0001) in 4 g/ day group and by 10.1 % (p = 0.0005), in 2 g/day

LDLc and HDLc no significant changes

Omega-3-acid ethyl esters plus SIM improved lipid and lipoprotein parameters to a greater extent than SIM alone

TG ; by (29.5 vs. 6.3 %) and VLDLc (27.5 vs. 7.2 %), a significant : in HDLc by (3.4 vs. -1.2 %), (all, p \ 0.001 vs. PL)

8 weeks of ol SIM 40 mg/day and dietary counseling, followed by 8 weeks of ran treatment with omega3-acid ethyl esters 4 g/day plus SIM 40 mg/day or PL plus SIM 40 mg/day

VaseptaÒ is indicated as an adjunct to diet to reduce TG levels in adult pts with severe (C500 mg/dL) hypertriglyceridemia

VaseptaÒ is indicated as an adjunct to diet to reduce TG levels in adults with TG C500 mg/dL

OmacorÒ found to be a safe and effective means of lowering TG over 1 year in pts with CHD and combined hyperlipidemia

TG ; by 20–30 % (p \ 0.005) and in VLDLc by 30–40 % (p \ 0.005). No significant changes in LDLc and HDLc

Omega-3-acid ethyl esters—OmacorÒ 2 g bid or PL for 24 weeks in a db trial. 46 pts went on active tx for a further 24 weeks in an open phase of the trial

Four capsules of OmacorÒ per day markedly ; TG concentrations in pts with severe hypertriglyceridemia

TG ; by 45 % (p \ 0.00001), TC by 15 % (p \ 0.001), HDLc : by 13 % (p = 0.014) and LDLc by 31 % (p = 0.0014)

LovazaÒ is indicated as an adjunct to diet to reduce TG levels in pts with TG C500 mg/dL

PUFAs of marine origin may be therapeutically useful for hypertriglyceridemia

Omega-3-acid ethyl esters—OmacorÒ (4 g/day) for 4 months

HDLc : by 9.1 %

LDLc : by 45 %

NC in TC, but both types of supplement increased HDL3 cholesterol. The fish, but not the vegetable, oil supplement led to a ; in plasma TG

15 g of fish oil (MaxEPAÒ) or 15 g of a blend of corn and olive oils daily for 4 weeks

Ingesting two capsules of any of these oils do not elicit the desired results

Mixed-isomer CLA supplementation had a favorable effect on serum insulin and but no CLA-specific effects on lipids

TC and LDLc ; in both groups and HDLc ; in women (p = 0.001, p = 0.02, p = 0.02, respectively) TC, HDLc, LDLc, and TG did not show significant differences among the four groups

Conclusions

Changes in lipids

Four groups: two 1-g capsules of PL, fish oil, flaxseed, or hempseed oil daily for 12 weeks

CLA or high-oleic acid sunflower oil 3.9 g/day for 12 weeks

Intervention


ran, db 292 factorial

Bosch et al. [88]

12,536 pts with diabetes or glucose intolerance

18,645 Japanese subjects with hypercholesterolemia

11,323 subjects with recent MI

3,851 subjects after MI

Subjects

Ethyl esters of n-3 PUFA 900 mg daily (n = 6,281) vs. insulin and standard care (n = 6,255). Median follow-up for 6.2 years

n-3 PUFA (850–882 mg of EPA ? DHA 1 g daily (n = 2,835) vs. vitamin E 300 mg daily (n = 2,830) vs. PUFA with vitamin E (n = 2,828) for 42 months EPA 1,800 mg daily with a statin (n = 9,326) vs. statin only (control, n = 9,319) for 5 years

Omega-3-acid ethyl esters (1 g/day for 1 year)

Intervention

HDLc small changes in both groups

NC in other lipid parameters

TG ; by 14.5 mg/dL in PUFA group vs. control

No significant differences in cardiovascular events

Major coronary events ; in EPA group

LDLc ; by 25 % in both groups TG ; by 9 % in EPA and 4 % in controls

Total mortality and cardiovascular mortality were ; with fish oil supplementation

Sudden cardiac death, total mortality, major cardiovascular events, and revascularization within 1 year were not reduced by the supplementation

Conclusions

NC in TC

LDLc did not significantly differ between the study groups. TG was low in both groups, with a small difference in favor of the omega group (1.37 vs. 1.43 mmol/L; p \ 0.01)

Changes in lipids

ALA alpha-linolenic acid, alphaTAC alpha tocopherol acetate, apo apolipoprotein, ATO atorvastatin, bid twice daily, BL baseline, CHD coronary heart disease, CLA Conjugated linoleic acid, db double-blind, DHA docosahexaenoic acid, EPA eicosapentaenoic acid, FA fatty acid, HDL high-density lipoprotein, HDLc high-density lipoprotein cholesterol, IDL intermediate-density lipoprotein, LDLc low-density lipoprotein cholesterol, MI myocardial infarction, NC no change, ol open-label, pc placebo-controlled, pg parallel-group, PL placebo, PS phytosterol, pts patients, PUFA polyunsaturated fatty acid, RA rheumatoid arthritis, ran randomized, SIM simvastatin, SNP single nucleotide polymorphism, TC total cholesterol, TG triglyceride, tx treatment, VLDLc very low-density lipoprotein cholesterol, : indicates increased, ; indicates decreased

The reader is also referred to other reviews and meta-analyses on this topic [50, 57–60]

ORIGIN trial

JELIS trial

ol, ran, active comparator controlled

Yokoyama et al. [87]

GISSI trial

Marchioli et al. [86]

ol, ran, pc

ran, db, pc

Rauch et al. [85]

OMEGA study

Design

References

Table 4 continued



supplementation for 3 months [69]. In another small randomized, double-blind, controlled clinical trial of 57 subjects with below-average HDLc concentrations (B44 mg/ dL [men] and B54 mg/dL [women], but C35 mg/dL), supplementation with 1.52 g/day of docosahexaenoic acid increased the LDLc level, but treatment had favorable effects on triglycerides, the triglyceride/HDLc ratio, and the fraction of LDLc carried by small, dense particles [70]. The subject baseline lipid profile and genetic or metabolic differences among study groups explain some of the inconsistency in the effects of omega-3 fatty acids on serum lipids. Genetic polymorphism may determine the effect of fish oil on metabolic profile [71]. Significant fish oil-related decrease in triglyceride and increase in HDLc levels occurs only in individuals with the GG variant of the 25444, 30294, -31118, or -33137 single nucleotide polymorphisms (SNPs) in the CD36 gene. The triglyceride-lowering effects of fish oil may be via stimulation of CD36 activity in extrahepatic tissues in individuals with the GG variants of these SNPs [71]. It is likely that the LDLc-lowering effects of (n-3) PUFA and phytosterols are synergistic, while the effects on triglycerides and HDLc are not [72]. In a 3-week randomized, double-blind, placebo-controlled study of 60 hyperlipidemic individuals, subjects were randomized to receive either sunola oil or 1.4 g/day (n-3) PUFA capsules with or without 2 g phytosterols per day while maintaining their usual diet. The combination of phytosterols and (n-3) PUFA reduced plasma total and LDLc by 13.3 and 12.5 %, respectively (p B 0.001), which differed from (n-3) PUFA alone (p B 0.001). The HDLc concentration increased (7.1 %; p B 0.01), and triglyceride concentration was lowered (22.3 %; p B 0.004) by (n-3) PUFA alone; similar changes were seen in combination with phytosterols, whereas phytosterol treatment alone had no effect [72]. However, in a randomized, double-blind trial of 56 participants, administration of 3 g/day of alpha-linolenic acid from flaxseed oil in capsules (n = 31) or placebo capsules containing olive oil (n = 25) for 26 weeks did not alter plasma lipoprotein concentration or LDL, HDL, or intermediate-density lipoprotein particle size [73]. The increase in HDLc levels is not seen in other studies with linoleic acid supplementation (Table 4). In a double-blind, randomized, controlled trial, 62 non-obese subjects (25 men, 37 women) received either 3.9 g/day conjugated linoleic acid (CLA) or 3.9 g high-oleic acid sunflower oil for 12 weeks. Supplementation with CLA had a favorable effect on serum insulin and non-esterified fatty acid response to oral glucose but serum total cholesterol and LDLc and HDLc concentrations decreased in both groups (p B 0.001, p B 0.02, p B 0.02, respectively) [74]. In another study, 86 healthy volunteers completed a 12-week

double-blind, placebo-controlled, clinical trial where they were randomly supplemented with two 1-g capsules of placebo, fish oil, flaxseed oil, or hempseed oil per day for 12 weeks [75]. No significant differences were shown in lipid parameters (total cholesterol, LDLc, HDLc, and triglycerides) among the four groups. The authors concluded that from a consumer’s perspective, ingesting two capsules of any of these oils in an attempt to achieve cardiovascular health benefits may not provide the desired results over a 3-month period [75]. The (n-3) PUFA is a potent modulator of lipoprotein metabolism, and the triglyceride-lowering effect of (n-3) PUFA has been used clinically to manage patients with hypertriglyceridemia [76–83] (Table 4). The effects of 4 g per day of omega-3-acid ethyl esters (LovazaÒ) were assessed in two randomized, placebo-controlled, doubleblind, parallel-group studies of 84 adult patients with baseline triglyceride levels between 500 and 2,000 mg/dL. The median triglyceride and LDLc levels in these patients were 792 and 100 mg/dL, respectively. Median HDLc level was 23.0 mg/dL. The placebo subtracted effect of this preparation was a 51.6 % reduction in triglyceride levels, 9.1 % increase in HDLc levels, and 49.3 % increase in LDLc levels [78]. As add-on treatment to simvastatin, 4 g per day of omega-3-acid ethyl esters in 254 adult patients with persistent high triglycerides (200–499 mg/dL) resulted in the following lipid changes: 23.2 % reduction in triglyceride levels, 4.6 % increase in HDLc levels, and a 3.5 % increase in LDLc levels [81]. The changes in the latter two variables did not reach statistical significance [81]. Icosapent ethyl (VascepaÒ) is another preparation of (n3) PUFA available by prescription. The effects of 4 g per day of icosapent ethyl was assessed in a randomized, placebo-controlled, double-blind, parallel-group study evaluating patients with fasting triglyceride levels C500 and B2,000 mg/dL with or without statin therapy [82]. The effect of this EPA-only omega-3 fatty acid preparation on plasma lipids included 33 % reduction in triglyceride levels, a 4.0 % (not significant) decrease in HDLc levels, and a 2.0 % (not significant) decrease in LDLc levels [82]. A similar study of 702 high-risk statin-treated patients with residually high triglyceride levels (C200 and \500 mg/dL) despite LDLc control (C40 and \100 mg/dL) confirmed the efficacy of icosapentanoic acid ethyl ester 2–4 g/day in lowering plasma triglyceride levels [83]. In the latter study, HDLc was reduced by 4.5 % (p \ 0.01) [83]. Although some epidemiological studies have shown that people who consume diets containing n-3 polyunsaturated fatty acids found in fish oils have reduced mortality from heart disease [84], the outcomes in interventional trials have not been consistent (Table 4). The effect of n-3-fatty acid ethyl esters-90 (1 g/day for 1 year) on the rate of


sudden cardiac death in survivors of acute myocardial infarction was studied in 3,851 patients [85]. During the 1-year follow-up, the rate of sudden cardiac death and other clinical events could not be shown to be reduced by the supplementation of n-3 fatty acids [85].This study was relatively small and the event rate during the 1-year followup was very low and therefore the study was not powered enough to detect any significant changes [85]. Two large randomized trials of omega-3 fatty acid supplementation in patients with recent myocardial infarction have demonstrated a survival advantage in those randomized to the fish oil supplement [86, 87]. However, in a recent study of 12,536 subjects with diabetes or glucose intolerance, fish oil supplementation (1-g capsule containing at least 900 mg of ethyl esters of n-3 fatty acids) was not associated with any clinically beneficial outcomes [88] (Table 4). It is noteworthy that most of the fish oil products available over the counter as nutritional supplements contain small amounts of active omega-3 fatty acids and would require the consumption of 10–20 pills a day to achieve measurable effects on plasma lipids. Whereas the effect of fish oil or omega 3 fatty acids on LDLc and triglycerides is robust and reproducible in various populations, their effects on plasma HDLc are variable, and the increase in HDLc level observed in some studies do not exceed 5–10 %. 4.5 Bile Acid Supplements Conjugated bile acids enhance digestion and absorption of fats and fat-soluble micronutrients. Additional benefits of bile acids include protecting intestinal mucosa from injury or infection by increasing resistance to injury-induced apoptosis, stimulating enterocyte proliferation, and increasing villus length [89]. In a murine model, taurodeoxycholic acid supplementation also results in an increased survival benefit [89]. The major bile components in commercially available bile acid supplements are glycocholate and taurocholate. A smaller component (5–10 %) is composed of unconjugated bile acids such as cholic acid and deoxycholic acid (DCA). Dietary cholic acid lowers plasma levels of apo A-I primarily by down-regulating apo A-I gene transcription partly through increasing apo A-I regulatory protein-1 (ARP-1), a negative regulator of the apo A-I gene in the mouse [90]. In high-fat/high-cholesterol fed mice, cholic acid supplementation lowered plasma HDLc levels and increased the levels of LDLc. However, high-fat diets without any added cholic acid, which more closely resemble human diets, increase levels of both HDLc and LDLc, suggesting that cholic acid may be responsible for the lowering of HDLc [90].

Quantitative and qualitative differences in intralumenal bile acids may affect cholesterol absorption and metabolism. In a small study of subjects (n = 11) taking 15 mg/kg/ day chenodeoxycholic acid (CDCA) or no bile acid for 20 days, there was no effect on plasma lipid concentrations, whereas in another study of nine subjects taking 15 mg/kg/ day DCA decreased (p B 0.05) plasma HDLc and tended to decrease (p = 0.15) LDLc [91]. In a recent double-blind, placebo-controlled, randomized study, 114 hypercholesterolemic adults received a yoghurt formulation containing microencapsulated bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242 twice per day over 6 weeks. The study found that consumption of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurt resulted in significant reductions in LDLc of 8.92 % (p = 0.016), total cholesterol of 4.81 % (p = 0.031), and non-HDLc of 6.01 % (p = 0.029) over placebo. Serum concentrations of triglycerides and HDLc were unchanged over the course of the study [92]. The authors concluded that the efficacy of microencapsulated BSH-active L. reuteri NCIMB 30242 yoghurt appears to be superior to traditional probiotic therapy and akin to that of other cholesterol-lowering ingredients [92]. It is not known if the observed effects were the result of quantitative or qualitative changes in bile acids. It appears that highly concentrated bile acid preparations when used for nutritional supplementation may cause lowering of HDLc. However, this has not been clinically documented within the range of consumption during supplementation, as the decrease in HDLc may well depend on the amount of cholic acid consumed. 4.6 Black Seed Oil/Black Currant Seed Oil Black seed has been used for a variety of ailments for over 2,000 years [93]. Recent studies have shown that black seed has anti-tumorigenic effects, due in part to its thymoquinone content, as well as anti-oxidative, anti-inflammatory, and glucose- and lipid-modulating effects [94– 100]. Black currant seed oil contains 14.5 % alpha-linolenic (18:3n3), 12.6 % gamma-linolenic (18:3n6), 47.5 % linoleic (18:2n6), and 2.7 % stearidonic (18:4n3) acids and, therefore, potentially could serve as an alternative to fish oil as an n-3 fatty acid source [101]. In cell cultures where the experimental conditions can be more tightly controlled and larger concentration of nutrients can be used, the black seed extracts significantly increased apo A-I production [102]. Black seed extracts prepared by organic and aqueous extraction methods increased apo A-I protein and mRNA levels in a hepatocyte cell line (HepG2 cells) and in an intestinal cell line (Caco2) [102]. This effect required a peroxisome proliferatoractivated receptor (PPAR)-a binding site in the apo A-I gene promoter [102].


In rats, black seed oil has been shown to lower total cholesterol, triglycerides, and LDLc levels [99]. In addition, black currant seed oil has a moderate immuneenhancing effect attributable to its ability to reduce prostaglandin E2 production [100]. In a randomized, double-blind, crossover study of 15 healthy women, 3 g/day of black currant seed oil for 4 weeks increased the proportion of 18:3n6 in triacylglycerols and cholesteryl esters, and that of dihomo-gammalinolenic (20:3n6) in triacylglycerols, cholesterol esters, and glycerophospholipids [98]. Serum levels of LDLc were lower after black currant seed oil compared with after fish oil (2.46 vs. 2.62 mmol/L, p \ 0.05), and the increase in apo A-I levels was higher (?0.10 vs. -0.04 mmol/L change before and after intervention), although there was no significant effect on HDLc [98]. Overall, despite the myriad of putative clinical effects of black seed oil, clinically there has not been conclusive evidence of its effects on HDLc. 4.7 Red Yeast Red yeast rice is the product of rice fermented with Monascus purpureus yeast. Red yeast supplements are different from red yeast rice sold in Chinese grocery stores. Red yeast is used medicinally, primarily for lowering plasma cholesterol level. In foods, red yeast is used as a food coloring such as for preparing Peking duck [103–105]. Biologic activity, potential side effects and drug interactions of the active ingredient in red yeast are similar to those of statins. Therefore, its medicinal use should be discouraged until the results of long-term studies are available. One of the most widely studied red yeast preparations is cholestin. Originally, it contained the same active ingredient found in the prescription drug MevacorÒ. However, following pressure from the US FDA, the manufacturer reformulated cholestin with a different active ingredient [106]. In a randomized controlled trial, 62 patients with dyslipidemia and a history of discontinuation of statin therapy due to myalgias were given 1,800 mg of red yeast (31 patients) or placebo (31 patients) twice daily for 24 weeks [107]. In the red yeast rice group, LDLc decreased by 1.11 mmol/L (43 mg/dL) from baseline at week 12 and by 0.90 mmol/L (35 mg/dL) at week 24 [107]. In the placebo group, LDLc decreased by 0.28 mmol/L (11 mg/dL) at week 12 and by 0.39 mmol/L (15 mg/dL) at week 24. The LDLc level was significantly lower in the red yeast rice group than in the placebo group at both weeks 12 (p B 0.001) and 24 (p B 0.011) [107]. Levels of HDLc, triglyceride, liver enzymes, creatine phosphokinase, and weight loss was not significantly different between groups [107].

In clinical trials, all red yeast rice products contained substantial amounts of monacolin K, the active ingredient that lowers LDLc. However, the consumer should be aware that some of the red yeast rice products on the market contain very little monacolin K and are therefore ineffective in lowering cholesterol. 4.8 Miscellaneous Supplements There is some evidence that sesame and its lignans induce beneficial changes in risk factors related to CVD. In a small study of 38 hyperlipidemic subjects, consumption of 40 g of white sesame seeds daily decreased the levels of serum total cholesterol, LDLc, and the ratio of total cholesterol/ HDLc [108]. Green tea may modulate insulin sensitivity, with epigallocatechin-3-gallate (EGCG) proposed as a likely health-promoting component [109]. Overweight or obese male subjects, aged 40–65 years, were randomly assigned to take 400-mg capsules of EGCG (n = 46) or the placebo lactose (n = 42) twice daily for 8 weeks. Consumption of EGCG had no effect on insulin resistance but did result in a modest reduction in diastolic blood pressure [109]. Spirulina maxima is a filamentous cyanobacterium used as a food supplement because of its high nutrient content [110]. It has been experimentally shown to possess several pharmacological properties. Oral spirulina maxima (4.5 g/ day for 6 weeks) supplied to a sample of 36 subjects reduced triglycerides and LDLc and HDLc values. It also reduced systolic and diastolic blood pressure [110]. Garlic has been shown to reduce blood pressure in hypertensive patients but not in normotensive subjects [111]. However, the evidence that garlic affects lipid parameters is inconclusive. In a meta-analysis, Khoo and Aziz [112] examined the effects of garlic supplements versus placebo in 13 randomized clinical trials of 1,056 healthy subjects and patients with CVD. Garlic supplements had no effect on total cholesterol, HDLc, LDLc, or triglyceride levels. In contrast, a recent study using highhydrostatic extracts from garlic increased HDLc levels in rats fed a high-fat diet [113]. These results suggest that the type of garlic preparation may alter its effects on lipid parameters. Artichoke leaf extracts have also been shown to lower total cholesterol levels [114]. Artichoke leaf extracts contain a mixture of polyphenolic compounds and several flavonoids, including apigenin and luteolin and their glycosides. A recent 8-week double-blind, randomized, placebo-controlled trial in subjects (n = 46 in each arm) with primary mild hypercholesterolaemia was associated with elevated HDLc levels and decreased total cholesterol and LDLc [115].


4.9 Micronutrients Some minerals and vitamins have been found to have an important modulatory role in apo A-I gene expression [116–122]. Chromium, vanadium, magnesium, and zinc have either insulinomimetic effects or have permissive effects on insulin action. Thus, it is not surprising that minerals can alter apo A-I expression. In particular, zinc deficiency causes downregulation of apo A-I expression [116, 117], while supra-physiologic concentrations of zinc as well as chromium or vanadium downregulate apo A-I promoter activity [120]. Low cellular copper status can enhance apo A-I mRNA production and increase apo A-I synthesis [118, 119]. The increase in apo A-I gene transcription was attributed to an elevated level of the regulatory factor HNF-4 [119]. Copper depletion did not alter apo B synthesis. Few randomized clinical trials have measured the effect of mineral supplementation on HDLc. The most commonly studied minerals are chromium and zinc. These studies have been summarized in previous reviews on micronutrients [123, 124]. These studies have found either no effect or modest stimulatory effect of chromium on HDLc level [123]. More recent studies in patient subgroups with high likelihood of specific mineral deficiency have shown more favorable results. For example, zinc supplementation in patients on hemodialysis who are prone to zinc deficiency may raise the HDLc level [125]. In this population, zinc 100 mg/day increased serum HDLc levels and apo A-I, and paraoxonase enzyme activity was significantly increased (p B 0.02). There was no significant change in the serum total cholesterol, triglyceride, or LDLc [125]. In a randomized trial of 69 subjects with type 2 diabetes, supplementation with magnesium, zinc, and vitamins C and E significantly increased HDLc and apo A-I levels [126]. In a placebo-controlled study of healthy middle-aged adults with moderately high cholesterol levels, copper supplementation (2 mg copper/day as copper glycinate) for 8 weeks raised activities for two copper enzymes, erythrocyte superoxide dismutase 1 and plasma ceruloplasmin, but did not significantly change total cholesterol, LDLc, and HDLc levels [127]. The effect of selenium on lipid profile was evaluated in a randomized controlled study of 501 subjects aged 60–74 years [128]. The subjects were randomized to receive selenium 100 lg/day (n = 127), 200 lg/day (n = 127), or 300 lg/day (n = 126), as high-selenium yeast or a yeast-based placebo (n = 121) for 6 months. The adjusted difference in change in total cholesterol levels for selenium compared with placebo was -0.22 mmol/L (-8.5 mg/dL; p B 0.02) for 100 lg of selenium per day; -0.25 mmol/L (-9.7 mg/dL; p B 0.008) for 200 lg of

selenium per day; and -0.07 mmol/L (-2.7 mg/dL; p B 0.46) for 300 lg of selenium per day [128]. Similar reductions were observed for non-HDLc levels. There was no apparent difference in change in HDLc levels with 100 and 200 lg of selenium per day. The total cholesterol/ HDLc ratio decreased progressively with increasing selenium dose (overall p B 0.01). The authors concluded that selenium supplementation has modestly beneficial effects on plasma lipids, but the clinical significance of the findings is unclear and should not be used to justify the use of selenium supplementation as additional or alternative therapy for dyslipidemia [128]. Plasma phosphate levels may also influence lipid metabolism [129]. In mice, dietary Pi restriction significantly increased high-cholesterol diet-induced hepatic lipid accumulation and decreased hepatic mRNA levels of several transcription factors, including PPARs and liver X receptors, known modulators of HDL and apo A-I [129]. However, the plasma levels of HDLc or the hepatic expression of apo A-I were not measured in this study [129]. Overall, supplementation with some minerals such as chromium, zinc, and possibly selenium in select populations prone to deficiencies in these minerals may have favorable effects on lipid profile, but the evidence is not conclusive enough to justify supplementation as therapy of dyslipidemia in general. Large interventional trials have found that supplementation with antioxidant vitamins do not protect against CVD [130, 131]. Indeed, some studies have found potential adverse effects. One small interventional trial found that antioxidants may partially blunt HDLc induction by simvastatin and niacin combination therapy [132]. Vitamins, notably those with antioxidative potential, may affect apo A-I gene expression. The apo A-I promoter is sensitive to the oxidative state of the cell, and some antioxidants, at high concentrations, can suppress apo A-I promoter activity in HepG2 cells [122]. In addition, liver X receptor (LXR)-alpha signaling is sensitive to antioxidants, and alpha-tocopherol has been shown to suppress ABCA1 expression and HDLc loading [133]. In human THP-1 cells, a foam cell model, alpha-tocopherol significantly reduced baseline expression and stimulation by oxidized LDL (oxLDL) of LXR-alpha activity, CD36, ABCA1, and ABCG1, thereby reducing cellular cholesterol efflux and potentially compromising reverse transport out of the vessel wall [133]. High-dose (1 g/day) vitamin C supplementation in vivo does not have consistent effects on plasma lipids or lipoprotein levels [134–136]. Thus, it appears that an optimal concentration of vitamins are needed for apo A-I gene expression. However, supplementation with excessive doses may lower plasma HDLc concentration. This adverse

Observational

Observational. CARDIA study

Observational study

ran, pc. CaD trial in Women’s Health Initiative

ran, pc

ran, db, pc

ran, db, pc

Auwerx et al. [140]

Fung et al. [141]

Maki et al. [142]

Rajpathak et al. [143]

Heikkinen et al. [144]

Maki et al. [145]

Anderson et al. [146]

89 women and 84 men of Pakistani origin living in Denmark

60 adults in USA with elevated waist circumference ([102 cm in men and [88 cm in women)

464 postmenopausal women in Finland. 320 completed the study

1,259 postmenopausal women in USA

257 men and women in USA

4,727 young men and women in USA

185 men, 173 women in Belgium

Subjects

NC in lipids

No change in HDLc, LDLc, or TG

Vitamin D, 10 or 20 lg/day vs. PL for 1 year

No adverse effect of vitamin D on lipids

Vitamin D did not affect CV risk markers such as lipids, BP, and weight

Vitamin D may have unfavorable effects on lipids. The relevance to CV risk is unknown

HDLc ; in vitamin D group (5.2 %) (p \ 0.001) and HRT ? vit D (3.7 %; p \ 0.046). LDLc decreased in HRT and HRT ? vitamin D group and : in vitamin D only group TG : in all groups

Dose of vitamin D may have been small

Low serum 25 OHD is associated with metabolic syndrome risk parameters

Independent of calcium levels, vitamin D levels correlate positively with HDLc and apo A-I Vitamin D intake inversely correlates with incident metabolic syndrome

Conclusions

No significant differences in lipid changes

Serum 25 OH vitamin D correlate directly with HDLc and inversely with TG

Supplemental and dietary vitamin D intakes inversely correlate with low HDLc (p \ 0.004)

Serum 25 OH vitamin D correlates with apo A-I (p \ 0.001) and HDLc

Changes in lipids

Vitamin D 1,200 IU ? MVM supplement daily vs. MVM only for 8 weeks

HRT with 2 mg estradiol valerate and cyproterone acetate vs. vitamin D 300 IU vs. HRT ? vitamin D vs. PL (calcium lactate 500 mg day) for 3 years

Vitamin D (400 IU) ? 1 g elemental calcium daily vs. PL for 5 years

Subjects were given food and dietary supplement questionnaires

Observed incidence of metabolic syndrome over 20 years

Survey of CV risk factors

Intervention

apo apolipoprotein, BP blood pressure, CAD calcium plus vitamin D, CARDIA Coronary Artery Risk Development in Young Adults, CV cardiovascular, db double-blind, HDLc high-density lipoprotein cholesterol, HRT hormone replacement therapy, LDLc low-density lipoprotein cholesterol, MVM multivitamin and mineral, NC no change, ol open-label, pc placebo-controlled, PL placebo, ran randomized, TC total cholesterol, TG triglyceride, tx treatment, : indicates increased, ; indicates decreased

Design

References

Table 5 The effect of vitamin D on the lipid parameters in observational and interventional trials



outcome was observed in a study of effects of vitamin E on plasma lipid status in Chinese women with metabolic syndrome [137]. The protective decreases in plasma total cholesterol were significant in 200 and 300 IU/day vitamin E groups compared with the 100 IU/day group (p B 0.05), but decreases in HDLc were also significant in all supplementation groups (p B 0.05). Plasma triglycerides were unaltered (p B 0.05) [137]. Like vitamins C and E, optimal vitamin D levels are necessary to support adequate apo A-I levels [138]. In HepG2 cells in culture, vitamin D suppresses apo A-I secretion and mRNA levels in a dose-dependent manner [139]. This was accompanied by a similar decrease in apo A-I promoter activity [139]. This suppression required a region within site A of the apo A-I gene promoter. However, vitamin D treatment did not alter transcription factor binding to site A, and therefore the effect was attributed to secondary alterations in coactivator/corepressor activities. Treatment with the vitamin D receptor antagonist ZK-191784 (ZK) inhibited the ability of 1,25-dihydroxyvitamin D3 to repress apo A-I promoter activity, while higher doses of ZK actually increased apo A-I promoter activity [139]. These changes may not be relevant clinically and can only be observed in supraphysiologic concentrations of vitamin D. In a study of a healthy Belgian population, those with high vitamin D levels also had the highest plasma apo A-I levels [140] (Table 5). In another study, Fung et al. [141] evaluated data from 4,727 Black and White young men and women from the CARDIA (Coronary Artery Risk Development in Young Adults) study to examine relations of dietary plus supplemental vitamin D intake with the incidence of metabolic syndrome. The intake of vitamin D from dietary and supplemental sources was inversely related to the 20-year cumulative prevalence of abdominal obesity (p B 0.05) and high glucose (p B 0.02) and low HDLc (p B 0.004) concentrations after adjustment for age, sex, race, education, center, and energy intake [141]. In a third observational study of 257 men and women in the USA, Maki et al. [142] found an independent and inverse association between serum 25-hydroxyvitamin D and HDLc as well as with the metabolic syndrome (Table 5). The interventional trials with vitamin D where HDLc and other lipid parameters were measured are summarized in Table 5. In the Women’s Health Initiative, 5 years of daily 1 g elemental calcium as carbonate plus 400 IU vitamin D3 supplementation did not alter any lipid variable [143]. However, vitamin D3 supplementation in postmenopausal women has recently been shown to be associated with adverse changes in serum lipoproteins [144]. The dose and duration of therapy may have a bearing on outcome. In one study, supplementation with 1,200 IU/day vitamin D3 for 8 weeks had no noticeable effect on HDLc level [145]. Andersen et al. [146] carried out a 1-year

randomized, double-blinded, placebo-controlled intervention study with two doses of vitamin D3 (10 and 20 lg/ day). The study subjects were 89 women (18–53 years of age) and 84 men (18–64 years of age) of Pakistani origin living in Denmark with low vitamin D status. This study did not find changes in total cholesterol, LDLc, HDLc, LDLc/HDLc ratio, very low-density lipoprotein (VLDL) cholesterol, or triacylglycerol after daily supplementation with vitamin D3 for 1 year [146] (Table 5). Vitamin A appears to have significant effects on hepatic but not intestinal apo A-I gene transcription, although apo A-I protein content does not change, suggesting additional regulation of post-transcriptional events [147–150]. The abundance of hepatic apo A-I mRNA of vitamin A-deficient rats was 2.2- to 6 times that of sufficient rats. These data indicate that apo A-I gene expression in vivo is sensitive to retinoid status [147]. Treatment of co-cultured rat hepatocytes with retinoic acid resulted in a specific decrease in apo A-I mRNA levels, whereas no marked difference in apo A-II mRNA levels was observed [150]. These results show that, contrary to primary pure hepatocyte cultures and hepatoma cell lines, co-cultures of rat hepatocytes with rat liver epithelial cells reproduce the in vivo results where retinoic acid appears to suppress the expression of apo A-I [149]. The clinical relevance of these observations is not known at the present time. Nicotinic acid and nicotinamide are forms of vitamin B3 and are generically referred to as niacin. Vitamin B3 is found in many foods, including yeast, meat, fish, milk, eggs, green vegetables, beans, and cereal grains and is a component of vitamin B complex supplements. Nicotinic acid is an effective drug for lowering hypertriglyceridemia and raising HDLc levels [151]. In contrast, nicotinamide has no effects on plasma lipid profile. Most niacin nutritional supplements contain nicotinamide, which has no effect on lipid parameters. In many other supplements that contain nicotinic acid, the amount (100 mg per pill) is often too small to effect a measurable change in plasma lipids. Fat oxidation requires carnitine, which can be obtained either from animal or dairy products in the diet or through synthesis in the body using both lysine and vitamin B6 [152]. In a 12-week randomized study of subjects with hypertriglyceridemia, vitamin B6 supplementation was associated with a significant reduction in total cholesterol and HDLc of *10 %. No major changes in the lipid profile were observed in the lysine and carnitine groups or when lysine was added to vitamin B6 [152]. 4.10 Non-Vitamin Antioxidants Quercetin is a flavonoid with potent antioxidant and antiinflammatory activity [153, 154]. The diverse biologic


effects of quercetin include inhibition of glucose transport in the intestine. In a double-blinded, placebo-controlled trial, supplementation of quercetin 150 mg/day in people with the metabolic syndrome decreased serum HDLc and apo A-I and increased the LDL:HDLc ratio in the apoE4 subgroup, whereas the apoE3 subgroup had no significant changes in these variables [153]. Quercetin has lipid-lowering effects in addition to its strong antioxidant effects. In a double-blind randomized study with 200 patients in each arm, quercetin supplementation for 2 months decreased cholesterol, triglyceride, and LDLc values with parallel increases in HDLc [155]. In another clinical trial, 93 overweight or obese subjects aged 25–65 years with metabolic syndrome traits were randomized to receive 150 mg of quercetin per day in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period [156]. In contrast to placebo, quercetin decreased systolic blood pressure by 2.6 mmHg (p B 0.01) in the entire study group and decreased serum HDLc concentrations (p B 0.001), while

Fig. 1 The effect of macronutrients and micronutrients on apolipoprotein A-I (apo A-I) and high-density lipoprotein (HDL) cholesterol. In the liver, several macronutrients and micronutrients increase or decrease apo A-I and HDL synthesis, while fewer nutrients affect apo A-I/HDL synthesis in the small intestine. Phytosterols and bile acids inhibit cholesterol absorption, altering plasma triglyceride and low-density lipoprotein cholesterol levels. Several nutrients increase or decrease HDL cholesterol levels, primarily by altering HDL particle metabolism and half-life. In vitro: studies performed in cultured hepatocytes or intestinal epithelial cells. In vivo: clinical trial results. apo A-I apolipoprotein A-I, CETP cholesterol ester transfer protein, FA fatty acid, HDL high-density lipoprotein, MUFA monounsaturated fatty acid, PUFA polyunsaturated fatty acid. Public domain illustration reproduced from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

total cholesterol, triglycerides, and the LDL:HDLc ratio were unaltered [156]. Berry-derived anthocyanin supplements have favorable effects on the serum lipid profile in dyslipidemic patients [157]. Anthocyanin supplementation in humans improves LDLc and HDLc concentrations and enhances cellular cholesterol efflux to serum. These benefits may be due to the inhibition of CETP [157]. In a double-blind, randomized, placebo-controlled trial, 120 dyslipidemic subjects (aged 40–65 years) were given 160 mg anthocyanins twice daily or placebo for 12 weeks. Anthocyanin consumption increased HDLc concentrations (13.7 and 2.8 % in the anthocyanin and placebo groups, respectively; p B 0.001) and decreased LDLc concentrations (13.6 and -0.6 % in the anthocyanin and placebo groups, respectively; p B 0.001) [157]. It is noteworthy that there may be differences among various antioxidant compounds, as some may have potent concomitant pro-oxidant activity and may have diverse effects on HDLc levels.


4.11 Alcohol and Wine Consumption Epidemiological studies have suggested that moderate wine consumption has cardioprotective effects [158]. This effect has been attributed to both components of wine: the alcoholic portion and, more importantly, the alcohol-free portion containing antioxidants including resveratrol, catechin, epicatechin, and proanthocyanidins [158]. Exposure of HepG2 and Hep3B cells to ethanol results in an increase of accumulation of apo A-I by 15–45 % in a dose-dependent manner [159]. None of the other major apolipoproteins, with the exception of apo B, were affected by these treatments. This effect was attributed to a metabolite of ethanol generated by the microsomal ethanoloxidizing system [159]. Moderate alcohol consumption (1–2 drinks per day) may decrease CVD risk by improving lipid profiles. In an observational study, alcohol consumption was associated with an increase of serum levels of both LpA-I and LpAI:A-II [160]. In postmenopausal women, plasma HDLc increased significantly after daily consumption of 30 g of alcohol. In addition, plasma apo A-I increased significantly and apo B decreased significantly [161]. Resveratrol is mainly found in the grape skin, whereas proanthocyanidins are found only in the seeds. Resveratrol is a natural antioxidant that enhances cholesterol efflux [162]. However, in a murine model of hyperhomocysteinemia, chronic administration of resveratrol had deleterious effects, as it significantly increased plasma homocysteine level, which was associated with a decreased serum paraoxonase-1 activity [163]. In a parallel, four-armed intervention study of 69 healthy men and women aged 38–74 years, wine consumption was associated with a significant (11–16 %) increase in fasting HDLc level [164]. However, the impact of wine on the measured cardiovascular risk factors was primarily explained by an alcohol effect rather than red wine contents of non-alcohol components [164].

5 Conclusions Several nutrients with diverse structures have been shown to modulate apo A-I, HDL, and HDLc levels (Fig. 1). These nutrients can be generally categorized by their main biologic activity to be either proestrogenic, nuclear receptor agonists, molecules with antioxidant activity, or those with mixed activities. However, there may be differences in the biologic effects of compounds within each category. For example, although dimethylsulfoxide (DMSO) and resveratrol induce apo A-I and ABCA1, respectively [162, 165], other antioxidants such as a-tocopherol and ascorbic acid have been shown to inhibit apo A-I gene expression in a hepatoma cell line maintained in culture [122].

Phytoestrogens present in soy preparations have been shown in some studies, but not in all, to improve HDLc (Table 2). In general, the stanols and sterols reduce LDLc by up to 15 % but have negligible effect on HDLc or triglyceride levels (Table 3). Several nutrients can be classified as natural nuclear receptor ligands. Examples include paxilline, a fungal metabolite that is a non-oxysterol LXR agonist that induces ABCA1 expression [166]. Another compound, guggulsterone, is a farnesoid X receptor (FXR) antagonist that has been shown to elevate plasma HDLc levels in mice but not in humans [55, 56]. The (n-3) PUFA have potent triglyceride-lowering effects, but their effect on HDL is clinically modest (Table 4). It is possible that changes in apo A-I gene expression induced by various nutrients may contribute to the plasma concentrations of HDLc and thereby may alter CVD risk. Although many nutrients have, at best, modest favorable effects on lipid profile, the HDLc blunting effect of commonly used antioxidant vitamins is disconcerting. Studies elucidating the nutrient effects on HDLc should help in the rational design of dietary recommendations to increase HDLc level and reduce CVD. Acknowledgments The authors report no conflicts of interest and have not received any funding for this manuscript

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Calcium supplements and serum cholesterol.

Postprandial effect of a high fat meal on plasma lipid, lipoprotein cholesterol and apolipoprotein measurements.

The effect of moderate alcohol intake on serum apolipoprotein A-I-containing lipoproteins and lipoprotein (a).

Serum total lipids, lipoprotein cholesterol, and apolipoprotein A in acute viral hepatitis and chronic liver disease.

Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism.

Lipoproteins of human peripheral lymph. Apolipoprotein AI-containing lipoprotein with alpha-2 electrophoretic mobility.

Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels.

Calcium supplements and serum cholesterol. Reply to S I Barr.

Differential effect of subspecies of lipoprotein containing apolipoprotein A-I on cholesterol efflux from cholesterol-loaded macrophages: functional correlation with lecithin: cholesterol acyltransferase.

apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease.

Differential role of apolipoprotein AI-containing particles in cholesterol efflux from adipose cells.

Phytotherapy and Nutritional Supplements on Breast Cancer.

The Tromsø Heart Study: serum apolipoprotein AI concentration in relation to future coronary heart disease.

Relationship of skeletal muscle fiber type to serum high density lipoprotein cholesterol and apolipoprotein A-I levels.

The effect of cholesterol feeding on primate serum lipoproteins. I. Low density lipoprotein characterization from rhesus monkeys with high serum cholesterol.

apolipoprotein a-I ratio, metabolic syndrome components, total cholesterol, and low-density lipoprotein cholesterol with insulin resistance in the population of georgia.

Increased mRNA levels of apolipoprotein M and apolipoprotein AI in the placental tissues with fetal macrosomia.

The clinical significance of preoperative serum cholesterol and high-density lipoprotein-cholesterol levels in hepatocellular carcinoma.

Apolipoprotein AI mRNA levels in WHHL rabbits.

An approach to the functional analysis of lecithin-cholesterol acyltransferase. Activation by recombinant normal and mutagenized apolipoprotein AI.

Variation at the apolipoprotein (apo) AI-CIII-AIV gene cluster and apo B gene loci is associated with lipoprotein and apolipoprotein levels in Italian children.

Studies on the formation, separation, and characterization of cyanogen bromide fragments of human AI apolipoprotein.

High level expression of human apolipoprotein A-I in transgenic rats raises total serum high density lipoprotein cholesterol and lowers rat apolipoprotein A-I.

Within-individual variation in serum cholesterol levels: association with DNA polymorphisms at the apolipoprotein B and AI-CIII-AIV loci in patients with peripheral arterial disease.