H YPOCHOLESTEROLEMIC E FFECT

1.9.1 H YPOCHOLESTEROLEMIC E FFECT

Oat products show prominent hypercholesterolemic effects in humans and in experimental animals, since they selectively lower the atherogenic serum or low- density lipoprotein (LDL) cholesterol concentration, while raising the protective or antiatherogenic or high-density lipoprotein (HDL) cholesterol concentration, or at least raising the ratio of HDL:LDL cholesterol concentrations. 8,136,222,223

A serum cholesterol-reducing effect was achieved in rats receiving variously prepared oat bran concentrates at about 20% concentration of the feed, an amount corresponding to 3.3% β-glucan in the feed; the serum total cholesterol levels were lowered 10 to 30% relative to the initial cholesterol levels and the levels of the control group receiving cellulose in the diet. 136 Moreover, several animal studies showed that barley grain can also offer a high-fiber, cholesterol-lowering alternative to oats. 8,57,222–225 After a 40-day feeding trial in rats by barley flour containing 6.2%

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total and 5.4% soluble β-glucans, significant reductions were observed in the levels of total cholesterol (39%), LDL cholesterol (61%), and triglycerides (21%), and

a significant elevation in the level of HDL cholesterol (34%) in serum, compared with a control casein diet. 224

The cholesterol-lowering activities of oats and barley are commonly attributed to the β-glucan fractions. Studies using purified oat β-glucan preparations strongly suggest that this is the most active component in oats, 226,227 although oat lipids and proteins, 227 as well as phytosterols, 228 tocotrienols, 223 and certain phenolics, 109 may also make some contribution to the cholesterol-lowering effects. Two different fac- tors, soluble fibers and tocotrienols (components of barley oil), have been implicated in the cholesterol metabolism of different animals and humans fed barley-based diets with an additive effect on serum lipid parameters. 12,186,223,229–232 Kalra and Jood 224 demonstrated that the content of total and soluble β-glucans in barley flour used as feed appeared to be strong predictors of cholesterol lowering in the serum and liver of rats.

In 1997, the U.S. Food and Drug Administration (FDA) approved a health claim for the use of oat-based foods for lowering the risk of heart disease and passed a unique ruling that allowed oat bran to be registered as the first cholesterol-reducing food at a dosage of 3 g of β-glucan per day from 0.75 g of β-glucan per serving. 233

A similar claim for Oatrim has recently been allowed. 234 Most clinical studies on cereal β-glucan have been with intact cell wall material, as in flours and bran. In their meta-analysis, Ripsin et al. 235 identified 12 studies that had investigated the relationship between consumption of oats and blood total cholesterol in 1503 free- living subjects with an age range from 23 to 73 years, and mean cholesterol levels between 4.6 and 7.1 mmol/l. A statistically significant decrease of –0.13 mm/l, with an average daily dose of oat soluble fiber of 3.2 g, was calculated for the 12 trials. In a subsequent meta-analysis report, Brown et al. 236 identified 25 trials for a total of 1600 subjects, including normal healthy individuals, hyperlipidemics, and dia- betics, within an age range of 26 to 61 years. The mean initial total, LDL, and HDL cholesterol values were 6.31, 4.40, and 1.28 mmol/l, respectively, and the amount of soluble fiber consumed daily ranged from 1.5 to 13.0 g. In the analysis of the practical dose range from 2 to 10 g/day of oat soluble fiber, there were significant reductions in blood total (–0.040 mmol/l per 1 g of fiber) and LDL (–0.037 mmol/l per 1 g of fiber) cholesterol. The triacylglycerols and HDL cholesterol were not significantly influenced. Bell et al. 217 summarized several clinical studies on choles- terol-lowering effects of various oat products, mostly oat bran, and reported that diets providing from 3.4 to 7.5 g oat β-glucans lower total serum cholesterol and LDL cholesterol in the ranges of 2 to 19% and 9 to 23%, respectively. Jenkins et al. 237 investigated the reduction of serum lipid risk factors for cardiovascular disease in hyperlipidemic adults consuming a test (high-fiber) or control diet for 1 month. The high-fiber diet included four servings/day of foods containing β-glucan that delivered 8 g/day more soluble fiber than did similar, unsupplemented foods in the control diet; test and control foods included breakfast cereals, breads, pasta meals, bakery products, crisps, and smoothies. The high-fiber diet compared with the control diet reduced total cholesterol by 2.1%, the total-to-HDL cholesterol ratio by 2.9%, and the LDL-to-HDL cholesterol ratio by 2.4%, whereas small reductions in blood

Cereal β -Glucans: Structures, Physical Properties, and Physiological Functions 49

pressure were also found after the high-fiber diet. These researchers applied the Framingham cardiovascular disease risk equation to the data and confirmed a reduc- tion in risk of 4.2%, which is likely to be significant on a population basis.

The relatively large amount of oat cereal that must be consumed to achieve an intake of 3 g of β-glucan led to the development of oat and barley β-glucan concentrates. Incorporation of an oat gum containing 66% β-glucan into rat diets at a 5% level showed reduction of serum and liver cholesterol and an increase in HDL cholesterol. 238 An extract of β-glucan from waxy hulless barley, containing 56% β-glucans, was incorporated into flour tortillas to provide 2 g of soluble fiber as β-glucan per serving. These flour tortillas were incorporated into rat diets and resulted in a reduction of plasma LDL cholesterol, although total cholesterol and

triglycerides did not differ. 239 Delaney et al. 13 formulated the experimental diet of hamsters to include β-glucan (2, 4, or 8 g/100 g) by addition of β-glucan concentrates prepared from oats and barley by water extraction and several purification steps and containing 65 and 78% β-glucans, respectively. For diets with a higher concentration of β-glucan than 4 g/100 g, dose-dependent decreases in plasma total and LDL cholesterol concentrations were observed in hamsters fed with the β-glucan compared with control hamsters; in this study, the choles- terol-lowering potency of β-glucans in hypercholesterolemic hamsters was approximately identical whether its origin was oat or barley. However, decreased HDL cholesterol concentrations were also observed in hamsters consuming high concentrations of β-glucan (8 g/100 g) from oats and barley. 13,228

Debate still exists as to the mechanisms by which a soluble fiber such as β- glucan exerts its hypolipidemic effect. Several authors reviewing this

subject 12,216–218,226,227,240 reported the following possible mechanisms: modification of bile acid (BA) absorption and metabolism, interference with lipid absorption and metabolism, production of short-chain fatty acids (SCFAs) from fiber fermentation in the colon, alterations in concentration of or sensitivity to insulin and other hormones, and indirect effect of replacement of dietary saturated fat and cholesterol by soluble fibers. The lowering cholesterol effect is believed to occur through a combination of these mechanisms rather than by a single mechanism.

It has been suggested that cereal β-glucans decrease absorption and readsorption of cholesterol, bile acids, and their metabolites by inducing high viscosity of the gastrointestinal tract contents, which reduces the diffusion rate of nutrients. The increase of the intestinal viscosity causes the digesta to hold on to extra water, which slows its movement. It has been demonstrated that β-glucanase supplementation in animal-fed diets increased lipids compared to diets without enzyme supplementa- tion. 225 Moreover, higher fecal excretion of neutral sterols and cholesterol 13,239,241 or decreases in liver cholesterol 222,224 have been demonstrated in trials with animals fed enriched β-glucan products, suggesting that β-glucans interfere with fat absorption. In rats fed with diets containing β-glucans from various oat bran concentrates, a dependence of the hypocholesterolemic action on extractability, viscosity, pseudo- plastic flow behavior, hydrodynamic properties, and molecular weight of β-glucans was found, supporting the hypothesis that the mechanism of action is largely based on the high viscosity induced by β-glucans. 136

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Moreover, fibers bind or trap bile acids in the digestive tract, which results in prevention of their absorption or reabsorption and thereby a reduction of the bile

acid pool circulating back to the liver. These actions stimulate production of more bile acids derived from cholesterol that is either made endogenously or captured from the circulation. It has been postulated that consumption of β-glucans increases the bile acid synthesis and excretion in the feces, as well as excretion in ileostomy

subjects. 240–245 Bowles et al. 131 showed by solid-state 13 C-NMR spectroscopy that there is no direct binding between bile acid salt molecules and specific sites on the

β-glucan polymer, supporting the proposition that the ability of β-glucan to inhibit readsorption of bile acids is a function of its high viscosity in aqueous solutions (possibly gel network formation in the intestinal environment), rather than any specific binding or complexation. However, these researchers noted that it is possible that binding might occur between β-glucan and micelles from bile and fatty acids,

rather than the isolated bile acid salts alone. On the other hand, Huth et al. 68 found that barley meal, as well as autoclaved and extruded products from barley, interacted with bile acids at pH values of 5.0 to 6.5, similar to those present in the small intestine, but there was no direct effect of the molecular weight of the β-glucan present in these products with the strength of the interactions, suggesting that viscosity in media might not play the dominant role in the binding mechanism of bile acids.

The fermentation of soluble fibers in the large intestine by colonic bacteria leads to the production of short-chain fatty acids (SCFAs), acetate, propionate, and

butyrate, which inhibit the hepatic cholesterol synthesis by limiting the action of 3- hydroxy-3-methylglutaryl (HMG)–coenzyme A (CoA) reductase, the rate-limiting enzyme required for cholesterol biosynthesis. In rats, diets enriched in cereal β- glucan increased the SCFAs in the colon and feces. 241 During in vitro fermentation of pancreatin-digested barley meal or barley extruded and autoclaved products with human feces flora, higher amounts of SCFA were found for the hydrothermally treated substrates; in this study, the solubility of β-glucan was increased by the

hydrothermal treatments. 68 A decrease of HMG-CoA reductase activity and an increase in cholesterol 7 -hydroxylase activity, an enzyme that breaks cholesterol in the synthesis of bile acids, were correlated with the presence of β-glucan in the chicken diet. 223

Hormone secretion from the gut and pancreas is altered by fiber intake, result- ing in improved insulin sensitivity and glucose tolerance. After fiber-supplemented meals, insulin secretion is significantly lower than after low-fiber meals providing the same quantities of nutrients. Soluble fibers delay gastric emptying and intes- tinal absorption of nutrients by developing high viscosity in the intestinal contents, thereby reducing postprandial hypoglycemia and insulin secretion. Carbohydrate and lipid metabolism are closely interrelated. Insulin has been reported to increase hepatic cholesterol synthesis; therefore, if fibers decrease carbohydrate absorption and insulin secretion, they may indirectly contribute to the hypocholesterolemic effects. 216,217,227,246,247

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