Kristina E. Andersson

Dietary oats and modulation of atherogenic pathways

Consumption of oats has long been known to lower plasma total and low-density lipoprotein (LDL) cholesterol levels, an effect usually attributed to the soluble fibers β-glucans. On the basis of this cholesterol-lowering effect, oats are ascribed cardiovascular health-promoting properties. However, besides cholesterol levels, effects of oats on parameters relating to atherosclerosis development have not been extensively investigated. Since oxidation of lipoproteins and inflammation are characteristics of atherosclerosis in addition to lipid accumulation in the vessel wall, micronutrients in oats (phytochemicals) with antioxidative and anti-inflammatory properties may contribute to an atheroprotective action. Here, we summarize evidence on antiatherogenic properties of oats obtained from in vitro assays, animal experiments, and human studies. Possible effects involving anti-inflammatory and antioxidative actions, as well as preservation of endothelial function, are considered in addition to those related to reduction of plasma cholesterol. Since results of in vitro assays with isolated oat components are difficult to compare with effects of whole oats in humans and experimental animals, more observational studies with isolated oat components or fractions of oats are warranted. Also, there is a lack of epidemiological studies focusing on effects of oat intake on the cardiovascular disease panorama.

Effects of oat bran, processed to different molecular weights of beta-glucan, on plasma lipids and caecal formation of SCFA in mice.

In the present study, we evaluated the cholesterol-lowering effects of different oat bran (OB) preparations, differing regarding their peak molecular weight (MWp) of beta-glucans (2348, 1311, 241, 56, 21 or < 10 kDa), in C57BL/6NCrl mice. The diets were designed to be atherogenic (0.8 % cholesterol and 0.1 % cholic acid), and they reflected the Western diet pattern (41 % energy fat). All OB preparations that were investigated significantly reduced plasma cholesterol when compared with a cellulose-containing control diet, regardless of the molecular weight of beta-glucan. Moreover, the difference in viscous properties between the processed OB (from 0.11 to 17.7 l/g) did not appear to play a major role in the cholesterol-lowering properties. In addition, there was no correlation between the molecular weight of beta-glucan and the amount of propionic acid formed in caecum. Interestingly, however, there was a significant correlation between the ratio of (propionic acid+butyric acid)/acetic acid and the MWp of beta-glucans: the ratio increased with increasing molecular weight. The results of the present study suggest that the molecular weights and viscous properties of beta-glucan in oat products may not be crucial parameters for their cholesterol-lowering effects.

Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice.

AIM The cholesterol-lowering properties of oats, largely ascribed to its contents of soluble fibers, beta-glucans, are well established, whereas effects on atherogenesis are less well elucidated. Oats also contains components with reported antioxidant and anti-inflammatory effects that may affect atherogenesis. In this work we examined effects of oat bran on plasma cholesterol, markers of inflammation, eNOS expression and development of atherosclerosis in LDL-receptor-deficient (LDLr(-/-)) mice. METHODS AND RESULTS Female LDLr(-/-) mice were fed Western diet+/-oat bran. Two concentrations of oat bran (40 and 27%) were compared regarding effects on plasma lipids. There was a dose-dependent reduction of plasma cholesterol by 42 and 20% with 40 and 27% oat bran, respectively. Both concentrations also lowered plasma triglycerides (by 45 and 33%) and relative levels of plasma LDL+VLDL. The reduction of plasma lipids was accompanied by increased faecal excretion of cholesterol and bile acids. Oat bran (40%) efficiently reduced atherosclerotic lesion area in the descending aorta (-77%) and aortic root (-33%). Plasma levels of fibrinogen and soluble vascular cell adhesion molecule-1 (VCAM-1) were significantly lower, and immunofluorescence of aortic sections revealed a 75% lower expression of VCAM-1 in oat-fed mice. The expression of eNOS protein in the aortic wall was increased in mice fed oat bran. CONCLUSIONS Oat bran supplemented to a Western diet lowers plasma cholesterol, reduces levels of some inflammatory markers, increases eNOS expression and inhibits atherosclerotic lesion development in LDLr(-/-) mice. It remains to be investigated which components in oats contribute to these effects.

Simultaneous intake of oat bran and atorvastatin reduces their efficacy to lower lipid levels and atherosclerosis in LDLr-/- mice

The present study aimed to investigate the effects of separate and simultaneous dietary intake of atorvastatin (ATO) and the soluble fiber oat bran on serum and hepatic lipid levels and the degree of atherosclerosis. Ninety female LDL-receptor-deficient (LDLr-/-) mice were fed a Western-type diet containing either low dose (0.0025%), high dose (0.01%) or no ATO, with or without oat bran (27%) (n=15 per group) for 16 weeks. Both ATO and oat bran were effective in reducing serum total cholesterol levels (low ATO: -5.48, high ATO: -9.12, oat bran: -3.82 mmol/l, compared to control (no ATO/no oat bran), all p<0.0001). When oat bran was added to a low dose ATO, the cholesterol-lowering effects of this combination were 50% smaller compared to the low dose ATO diet alone (between-group difference: 2.77 mmol/l, p=0.002), whereas total cholesterol decreased to a similar extent in the groups fed a high dose ATO, with or without oat bran (between-group difference: 1.10 mmol/l, p=0.21). Serum LDL- and HDL-cholesterol, triglycerides, hepatic lipid levels and atherosclerotic lesion development showed a similar pattern. In conclusion, the efficacy of oat bran and atorvastatin to lower lipid levels and atherosclerosis is reduced after simultaneous intake. We hypothesize that oat bran inhibits the intestinal absorption of atorvastatin, and consequently its cholesterol-lowering effects. The effects are likely dependent on the type of statin and dietary fiber, and on the relative timing of intake of the statin and the dietary fiber. Future studies should focus on these aspects to provide further insight into the exact mechanism of this food-drug interaction.

Effects of oats on plasma cholesterol and lipoproteins in C57BL/6 mice are substrain specific.

Cholesterol-lowering effects of oats have been demonstrated in both animals and human subjects. However, the crucial properties of oat-containing diets that determine their health effects need to be further investigated to optimise their use. A mouse model would be a valuable tool, but few such studies have been published to date. We investigated the effects of oat bran on plasma cholesterol and lipoproteins in two substrains of C57BL/6 mice. Western diet was made atherogenic by the addition of 0.8 % cholesterol and 0.1 % cholic acid. After 4 weeks on atherogenic diet, total plasma cholesterol had increased from 1.86-2.53 to 3.77-4.40 mmol/l. In C57BL/6NCrl mice, inclusion of 27 and 40 % oat bran reduced total plasma cholesterol by 19 and 24 %, respectively, reduced the shift from HDL to LDL+VLDL and caused increased faecal cholesterol excretion. There was no effect of oat bran on plasma levels of the inflammatory markers fibrinogen, serum amyloid A or TNF-alpha. Contrary to findings in C57BL/6NCrl mice, there was no sustained effect of oat bran (27 or 40 %) on plasma cholesterol in C57BL/6JBomTac mice after 4 weeks of feeding. Thus, C57BL/6NCrl mice fed an atherogenic diet are a good model for studies of physiological effects of oats, whereas a substrain derived from C57BL/6J, raised in a different breeding environment and likely possessing functional genetic differences from C57BL/6N, is considerably less responsive to oats. The present finding that two substrains of mice respond differently to oats is of practical value, but can also help to elucidate mechanisms of the cholesterol-lowering effect of oats.

Effects of Pediococcus parvulus 2.6 and its exopolysaccharide on plasma cholesterol levels and inflammatory markers in mice

Intake of dietary fibres may reduce the prevalence of physiological risk factors of the metabolic syndrome, such as high plasma lipid levels and low-grade inflammatory state. Dietary fibres are usually of plant origin however microbial exopolysaccharides (EPSs) have analogue structures that could potentially exert similar physiological effects. Pediococcus parvulus 2.6 (Pd 2.6) excretes a ropy EPS and has previously shown probiotic potential. The aim of this work was to evaluate physiological effects of Pd 2.6 and its EPS in vivo. The live Pd 2.6 (both the ropy and non-ropy isogenic variant) and its purified EPS were fed to hypercholesterolemic LDL-receptor deficient mice for 6 weeks to investigate their effects on cholesterol levels and the inflammatory tone of the animals. Both variants of Pd 2.6 survived passage through the mouse gut fulfilling an important criterion of probiotics. The ability to produce EPS was conferring an advantage to survival (faecal recovery of 3.7 (1.9-8.7) vs. 0.21 (0.14-0.34) *108 CFU, P < 0.001, median and 25th and 75th percentiles). The ropy Pd 2.6 decreased the levels of soluble vascular cell adhesion molecule-1 compared to the EPS alone (591 ± 14 vs. 646 ± 13 ng/ml, P < 0.05). An increase in liver weight in mice fed the purified EPS was observed, but with no change in liver lipids. No changes in blood lipids were detected in any group. Further the EPS induced growth of the caecal tissue and increased the amount of caecal content showing bulking properties like that of a dietary fibre.

Late onset vascular dysfunction in the R6/1 model of Huntington's disease.

Huntingtons disease is a neurodegenerative disorder that also gives raise to widespread changes in peripheral organs and tissues. We tested the hypothesis that vascular dysfunction may occur in Huntingtons disease by studying R6/1 mice which express exon 1 of the mutant huntingtin gene. We assessed arterial function in R6/1 and wild type (WT) mice using myography. Arterial contractility was largely unaltered in R6/1 arteries at 15 and 32 weeks of age. By 40 weeks, contractility was impaired irrespective of which vasoconstrictor we tested. Endothelium-dependent relaxation was not affected, and we observed no changes in arterial geometry or expression of contractile proteins, such as myosin regulatory light chains or smooth muscle α-actin. The frequency of calcium oscillations in R6/1 arterial smooth muscle cells was higher than in WT control tissue, whereas myosin phosphorylation was unaltered. Impairment of force by the mitochondrial inhibitors cyanide and rotenone was less pronounced in R6/1 than in WT arteries and mitochondria were enlarged, in keeping with an effect related to altered mitochondrial function. Our results reveal that arteries in the R6/1 model of Huntingtons disease exhibit an age-dependent impairment of contractility and that they depend less on mitochondrial function when they contract.

Wholegrain oat diet changes the expression of genes associated with intestinal bile acid transport

SCOPE The molecular mechanisms underlying the cholesterol-lowering properties of oats are only partly known. To study possible pathways involved, we investigated gene expressions in the liver and small intestine of mice fed oats. METHOD AND RESULTS Cholesterol and bile acids were analyzed in plasma and feces from LDL-receptor deficient (LDLr-/- ) mice fed Western diet with wholegrain oats. A transcriptome analysis of mRNA from liver and jejunum was performed together with quantitative RT-PCR. Oat-fed mice had lower levels of plasma lipids and increased levels of bile acids and cholesterol in feces compared with controls. Two hundred thirty nine genes in jejunum and 25 genes in liver were differentially expressed (FDR corrected p < 0.05). The most affected biological process in jejunum was lipid biosynthesis and regulation. The apical sodium-dependent bile acid transporter (ASBT, Slc10a) and the intracellular bile acid binding protein (Fabp6) were both upregulated, whereas small heterodimer partner-1 (Shp-1) and apolipoprotein CII (Apoc2) were downregulated. CONCLUSIONS Whole oats attenuated responses typically induced by high-fat diet. Increased expression of genes for intestinal bile acid uptake following oat consumption suggests retention in the gut lumen rather than decreased uptake capacity as cause for the increased bile acid excretion and the concomitant reduction of plasma cholesterol.