New research in molecular nutrition indicates the importance of diet, including a burgeoning array of functional foods, for reducing cholesterol levels. Ronald P Menskink, PhD, and colleagues Jogchum Plat, PhD, and Daniëlle AJM Kerckhoffs, MSc, explore.
Coronary heart disease (CHD) is still the leading cause of morbidity and mortality in the Western world, but its prognosis has improved substantially during the past decades in part because of our better understanding of CHD's underlying pathology. Researchers have identified many factors, both modifiable and nonmodifiable, that are associated with CHD risk. Much research on CHD risk has focused specifically on the distribution of cholesterol through different lipoproteins. For example, elevated low-density lipoprotein (LDL) levels or low high-density lipoprotein (HDL) levels signal an unfavourable fasting lipoprotein profile. Moreover, evidence is mounting that increased serum triacylglycerol concentration is positively related to cardiovascular risk.1
Diet is a cornerstone for improving unfavourable lipoprotein profiles. Studies continue to support dietary advice that focuses on reducing cholesterol as well as saturated and trans fatty acid intake; eating more vegetables, fruits and whole grains; and preventing obesity.2,3 By achieving these goals, people can often reduce their LDL cholesterol by 10 per cent to 15 per cent. Functional foods offer the promise of further lipid profile improvements.
Most promising for functional foods development are soy protein, soluble fibre, fish oils and plant sterols or stanols, all of which help improve serum lipoprotein profiles.
The US Food and Drug Administration (FDA) has approved a health claim that 25g soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce heart disease risk.4 Several dietary intervention trials have shown that when soy consumption increases, serum lipoprotein profiles improve. The precise mechanism for this effect is unknown, but researchers have suggested several possible explanations, including a higher bile acid excretion or enhanced LDL receptor activity.5
Researchers who conducted a meta-analysis published in The New England Journal of Medicine in 1995 estimated that an average daily intake of 47g soy protein, instead of animal protein, lowered serum total and LDL cholesterol concentrations by nine per cent and 13 per cent, respectively, and triacylglycerol by 11 per cent.6 HDL cholesterol concentrations were not affected. Researchers found subjects with high cholesterol levels to be more responsive than those with mildly elevated levels.
In fact, most individual studies involving soy-containing products and subjects with normal or slightly increased total cholesterol levels did not demonstrate a significant serum lipoprotein profile improvement. Therefore, it remains to be resolved whether soy-containing products are only beneficial for significantly hyperlipidemic subjects. Further, it remains to be determined whether soy protein's benefits are the result of soy protein per se or of soy's isoflavones. In the aforementioned meta-analysis, the researchers could not demonstrate a difference in effect between isolated soy protein and textured soy protein. In other studies examined in the meta-analysis, however, researchers suggested that soy's isoflavones account for up to 60 per cent of soy's cholesterol-lowering effects.6
The effects of isolated isoflavones on serum LDL cholesterol concentrations in hypercholesterolemic subjects are, however, not consistent. In one randomised, controlled clinical trial involving 156 healthy men and women, researchers found a significant reduction in serum LDL cholesterol concentrations when subjects ate soy protein with isoflavones compared with soy protein depleted of isoflavones.7 Further, essentially the same findings were described in hypercholesterolemic postmenopausal women.8 In contrast, a third trial with a similar approach did not confirm these findings. In fact, both the isoflavone-rich and isoflavone-poor soy proteins significantly improved the serum lipoprotein profile when compared with protein from casein and non-fat dry milk.9 Also, 80mg isoflavones in supplement form did not induce a significant cholesterol-lowering effect in menopausal and perimenopausal women with normal cholesterol levels.10 However, systemic arterial flexibility was significantly improved.
These conflicting findings do not strongly support the notion that it is just the isoflavones responsible for the potential cholesterol-lowering effect of soy-containing products. It is possible, however, that isoflavones are only effective in combination with other components from soy, such as proteins or saponins.
Dietary fibres, which are resistant to digestion by enzymes in the gastrointestinal tract, can be divided into water-soluble and insoluble fibres. The water-soluble (or viscous) fibres, in particular, have long been recognised for their ability to lower serum cholesterol concentrations. The effective fibre from oats is beta-glucan.11 In 1997, the US FDA approved the health claim that "a diet high in soluble fibre from whole oats and low in saturated fat and cholesterol may reduce the risk of heart disease."12
To achieve a clinically relevant reduction in total serum cholesterol concentrations, a person would have to eat at least 3g beta-glucan per day from oats. Based on a meta-analysis, researchers estimated that such an amount of soluble fibres from oats lowered serum cholesterol concentrations an average of 0.13 mmol/L (5mg/dL) in subjects with a serum cholesterol concentration below 5.9 mmol/L (227mg/dL) and by 0.41 mmol/L (16mg/dL) in hypercholesterolemic subjects.13 In general, researchers did not observe an effect on HDL cholesterol or triacylglycerol concentrations. LDL cholesterol reductions were found to be dose dependent.13,14
Researchers have proposed several mechanisms to explain the cholesterol-lowering effect of beta-glucan. One hypothesis proposes that beta-glucan increases bile acid synthesis because the enterohepatic circulation of bile acids is reduced by intestinal binding of bile acids to beta-glucan.15,16 Alternatively, it is possible that the viscous beta-glucan acts as a physical barrier in the intestinal tract, blocking absorption of bile acids and cholesterol. Other researchers have postulated that soluble fibres are bacterially fermented in the colon, leading to the production of short-chain fatty acids, such as propionate, which may lower hepatic cholesterol synthesis.17
Researchers also have suggested that, particularly in the postprandial state, soluble fibres lower insulin levels, which is also known to lower cholesterol synthesis.18 However, researchers have not found changes in serum cholesterol-precursor concentrations after oat consumption, suggesting that these latter two explanations are not likely correct.19
Numerous well-controlled trials did not demonstrate a beneficial effect of beta-glucan from oats on the serum lipoprotein profile.20-23 Possible explanations for these inconsistent results may be differences in the viscosity of the beta-glucan or detrimental effects of food manufacturing on its viscous characteristics. Elucidating the exact mechanism underlying the cholesterol-lowering effects of beta-glucan may be helpful to explain these apparent discrepancies.
In addition to the soluble fibres from oats, viscous fibres from other sources also may have favourable effects on serum lipoprotein profiles. Beta-glucan from barley and yeast sources, for example, also appear to be effective.24,25
Also in this respect, the US FDA has approved a cholesterol-reducing health claim for psyllium, a soluble fibre isolated from the psyllium seed husk (PSH).26 To achieve a significant reduction in total cholesterol levels, subjects must take at least 10.2g PSH supplying 7g soluble fibre daily (four servings each containing 1.7g soluble fibre) as part of a diet with low saturated fat and cholesterol levels. From three different meta-analyses, taking 910g PSH a day lowers serum LDL cholesterol concentrations by 6.0-7.4 per cent. In contrast to beta-glucan, PSH-induced cholesterol reductions do not seem to be associated with initial cholesterol concentrations.27-29
Two characteristic fatty acids from fish are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both EPA (C20:5, n-3) and DHA (C22:6, n-3) are highly unsaturated. Strictly speaking, these two fatty acids are not essential for humans, who can synthesise EPA and DHA from alpha-linolenic acid (C18:3, n-3), a fatty acid mainly found in vegetables. These rates, however, are low.30
Epidemiological studies do suggest that eating more fish has a protective effect, reducing CHD risk.31 Indeed, in dietary intervention studies, researchers have demonstrated that EPA plus DHA lower fasting and postprandial serum triacylgly-cerol concentrations, especially in hypertriglyceridemic subjects; however, if anything, fasting serum LDL and HDL cholesterol concentrations increase slightly.32 These effects on triglycerides are observed at intake levels that can hardly be achieved with regular foods. It is therefore questionable if the possible cardioprotective effect of fish oil can be fully explained by its effects on the serum lipoprotein profile. For example, EPA and DHA also affect other processes such as thrombotic function,33 inflammation34,35 and modification of Na+ channels to prevent ventricular fibrillation36 and consequent sudden cardiac death.37,38 Thus, despite compelling evidence, it is still not known if—and at what intake levels—fish oil affects CHD risk and is hard to ascertain because the precise mechanism of action is not known.
Diet Is The Cornerstone
Improving diet goes a long way toward improving an unfavourable lipoprotein profile, often decreasing LDL cholesterol levels an average of 10 per cent to 15 per cent. HDL cholesterol and triacylglycerol concentrations also may be favourably affected, especially after weight loss. However, for those who do not achieve the desired lipoprotein profile despite strict dietary compliance, functional foods can be beneficial. Soy protein, beta-glucan and psyllium, in particular, are dietary components that may help reduce serum LDL cholesterol concentrations. Diets low in saturated fat, trans fatty acids and cholesterol, along with adequate amounts of soy protein and viscous fibres, may lower LDL cholesterol concentrations between 30 per cent and 35 per cent.39
It is important not only to identify the active food components, but also to understand the mechanisms underlying the effects of these compounds. For this, detailed studies at the molecular level are needed. This relatively new area of molecular nutrition is essential to understanding how nutrition affects metabolic processes and ultimately health. This information is also needed to substantiate possible health claims. Finally, attention should be paid not only to effects on the lipoprotein profile, but also on other health-related parameters that decrease cardiovascular disease risk.
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