Fady Y. Ntanios

Dietary phytosterols as cholesterol-lowering agents in humans

Phytosterols (plant sterols), abundant in fat-soluble fractions of plants, are consumed at levels of 200-400 mg/day in Western diets. Chemically resembling cholesterol, phytosterols inhibit the absorption of cholesterol. Phytosterol consumption in human subjects under a wide range of study conditions has been shown to reduce plasma total and low density lipoprotein (LDL) cholesterol levels; however, the response varies widely. Greater cholesterol-lowering efficacy occurs with consumption of the saturated phytosterol sitostanol versus sitosterol or campesterol. Most studies report no effect of phytosterol administration in high density lipoprotein (HDL) cholesterol or triglyceride levels, although certain evidence exists for an HDL cholesterol raising effect of sitostanol. Phytosterol absorption is limited, although serum phytosterol levels have proven to be important indicators of both cholesterol absorption and synthesis. Serum phytosterols correlate with HDL cholesterol level. In addition, higher phytosterol/cholesterol ratios appear in HDL versus LDL particles, suggesting the existence of an intrinsic phytosterol action, in addition to the extrinsic effect on cholesterol absorption. In conclusion, addition to diet of the phytosterol sitostanol represents an effective means of improving circulating lipid profiles to reduce risk of coronary heart disease.

Dietary sitostanol reciprocally influences cholesterol absorption and biosynthesis in hamsters and rabbits

The aim of this study was to examine the efficacy of variable dietary sitostanol (SI) concentrations on cholesterol absorption, synthesis and excretion rates in two animal models. Hamsters and rabbits were fed semi-purified diets supplemented with cholesterol and 1% (w/w) phytosterols containing either 0.007, 0.17, 0.8 or 1% (w/w) SI. The control (0% (w/w) SI) groups consumed the same diets but no phytosterols were added. The dual-isotope plasma ratio of [13C]- and [18O]cholesterol and deuterium incorporation methods were applied to measure simultaneously cholesterol absorption and fractional synthesis, respectively. Plasma total cholesterol levels were lower in rabbits and hamsters fed 0.8 and 1% (w/w) SI, respectively, as compared to their controls. Percent cholesterol absorption was lower (P = 0.03) in hamsters fed 1% (w/w) SI (42.5 +/- 13.3%) than control (65.1 +/- 13.4%). Moreover, cholesterol excretion in the feces was 77 and 57% higher (P = 0.017) in the 1% (w/w) SI- relative to control- and 0.17% (w/w) SI-fed groups, respectively. In rabbits, cholesterol excretion was 64% higher (P = 0.018) in 0.8% (w/w) SI- compared with control-fed groups. Fractional synthesis rate was higher (P = 0.033) in hamsters fed 1% (w/w) SI (0.116 +/- 0.054 pool day(-1)) as compared to control (0.053 +/- 0.034 pool day(-1)). However, cholesterol synthesis rates did not vary among groups fed variable concentrations of SI. In rabbits, percent cholesterol absorption and its fractional synthesis rate varied but did not reach significance. Fractional synthesis rate in hamsters was correlated (r = -0.32, P = 0.03) with percent cholesterol absorption. In conclusion, dietary SI exhibited a dose-dependent action in inhibiting cholesterol absorption while increasing cholesterol excretion and upregulating cholesterogenesis in hamsters resulting in lower circulating lipid levels.

Dietary sitostanol reduces plaque formation but not lecithin cholesterol acyl transferase activity in rabbits.

The effects of graded amounts of dietary sitostanol (0.01, 0.2 and 0.8% (w/w)) were examined on plasma lipid-profile, coronary artery plaque development and lecithin:cholesterol acyl transferase activity in male New Zealand White rabbits given semi-purified diets for 10 weeks. All diets provided < 10% energy in the form of fat and contained 0.5% (w/w) cholesterol (C). Rabbits fed the semi-purified diet with 0.8% (w/w) (0.64 g/day) sitostanol had lower plasma total cholesterol (TC) (p = 0.006) (15.2 +/- 4.80 mmol/l) and very low-density lipoprotein-cholesterol (VLDL-C) (p = 0.007) (6.31 +/- 3.11 mmol/l) levels compared to the atherogenic control group (n = 6) (29.6 +/- 5.52 and 17.16 +/- 7.43 mmol/l, respectively). Dietary sitostanol at 0.8% (w/w) depressed plaque accretion in coronary arteries (p = 0.0014) and ascending aorta (p = 0.0004) compared with the atherogenic control, 0.01 and 0.2% (w/w) sitostanol-fed groups. No differences (p = 0.24) in the activity of lecithin:cholesterol acyl transferase (LCAT) were observed across groups, although plasma cholesterol fractional esterification rate was higher (p = 0.004) in the 0.8% (w/w) sitostanol fed animals compared with the atherogenic control. Significant negative correlations were demonstrated between sitostanol intake and plasma TC, LDL-C and VLDL-C levels. Hepatic campesterol levels were correlated (r = 0.3, p = 0.03) with plasma but not hepatic TC concentrations. These results demonstrate that dietary sitostanol at a concentration of 0.8% (w/w) or 0.64 g/day lowered plasma cholesterol levels and depressed atherosclerosis development in rabbits, but did not alter LCAT activity.

Effects of variable dietary sitostanol concentrations on plasma lipid profile and phytosterol metabolism in hamsters

To examine how variable sitostanol (SI) levels in phytosterol-supplemented diets influence plasma and hepatic lipid concentrations, fifty hamsters were divided into five groups and fed semipurified diets containing 0.25% (w/w) cholesterol for 45 days ad libitum. Four groups were fed this diet with 1% (w/w) phytosterol mixtures which contained 0.01% (w/w) SI derived from soybean, 0.2% (w/w) SI derived from tall oil, 0.2% (w/w) synthetic SI mixture (SIM) and 1% (w/w) pure SI, respectively. A control group did not receive phytosterols. Dietary SI supplementation at 1% (w/w) decreased total and non-apolipoprotein-A cholesterol levels in plasma by 34% (P=0.001) and 55% (P=0.04), respectively, whereas mean plasma total cholesterol level in the 0.2% (w/w) SI group was 23% (P=0.001) lower than that of the control group. Conversely, plasma lipid profile in hamsters fed 1 or 0.2% (w/w) SI did not differ from the 0.01% (w/w) SI group. Liver weights were 15 and 20% (P=0.012) higher in the control group compared with those fed 0.01% and 1% (w/w) SI, respectively, while the hepatic cholesterol content in the control group was greater (P<0.0001) than that of all other groups. Plasma campesterol levels were higher (P=0.04) in the 0.01% and 0.2% (w/w) SI fed groups than in the control, 0.2% (w/w) SIM and 1% (w/w) SI groups. Hepatic sitosterol content was elevated (P=0.002) in the SIM fed group compared to other groups. We conclude that dietary SI effect is proportional to its concentration in phytosterol mixtures and in the diet. Dietary SI lowered plasma cholesterol levels at concentrations higher than 0.2% (w/w) in hamsters. (c) 1998 Elsevier Science B.V.

Effects of various amounts of dietary plant sterol esters on plasma and hepatic sterol concentration and aortic foam cell formation of cholesterol-fed hamsters ☆

Dietary intake of plant sterol esters (PSE) lowers plasma LDL-cholesterol (LDL-C), but can modestly increase plasma plant sterol concentrations. The objective of the present study was to investigate the impact of increasing doses of dietary PSE on plasma and liver sterol concentrations as well as on aortic foam cell development as a marker of atherogenesis. One-hundred and twenty F(1)B hybrid Syrian golden hamsters (20 per group) were fed a basal atherogenic diet containing 30% of energy as fat and 0.12% (w/w) cholesterol and supplemented with 0, 0.24, 0.48, 0.96, 1.92 and 2.84% (w/w) PSE. After 12 weeks, plasma total cholesterol (TC) and LDL-C were significantly lower in the groups fed PSE compared with control. Plasma plant sterol concentrations increased with increasing dietary PSE intake up to the dietary level of 1.92% and then reached a plateau. On the other hand, hepatic campesterol and sitosterol concentrations plateaued at 0.24% PSE. Foam cell presence in the aortic arch showed an inverse relationship with dietary PSE intake (P<0.0001). Lipid-filled foam cell areas of hamsters receiving 0.24, 0.48 or 2.84% PSE were approximately 70, 90 and 100% smaller than in control hamsters fed no PSE. In summary, dietary PSE lowered plasma TC and LDL-C. Despite an increase in plasma plant sterol concentrations they did not contribute to aortic foam cell development. In fact dietary PSE significantly inhibited aortic foam cell formation. This study supports the concept that PSE through their cholesterol-lowering action prevent development of atherogenesis in this animal model.

Gender effects of tall oil versus soybean phytosterols as cholesterol-lowering agents in hamsters.

To examine the effect of gender on the mechanisms of action of phytosterols extracted from tall oil (TO) and soybean (SB) on cholesterol and phytosterol metabolism, male and female hamsters were fed cholesterol-enriched diets containing 0.5 or 1% (w/w) TO or SB phytosterols for 90 days. Plasma lipoprotein cholesterol profile and tissue phytosterol and cholesterol biosynthesis levels were determined. Mean plasma total-cholesterol level in females fed 1% (w/w) SB was reduced (p<0.05) by 44%, while in males it was lowered (p<0.05) by 25% compared with their respective controls. Moreover, mean plasma total-cholesterol level was reduced (p<0.05) in male hamsters by -31% and female hamsters by -32% when fed 1% (w/w) TO. Cholesterol biosynthesis was higher (p<0.05) by twofold in groups fed TO at 0.5 and 1% (w/w) concentrations, compared with SB. Hamsters fed TO at 0.5 and 1% (w/w) levels also had higher (p<0.05) hepatic and enterocytic campesterol contents than SB-fed animals. These findings demonstrate gender differences in cholesterol metabolism in TO- and SB-fed hamsters. The results suggest that TO, conversely to SB phytosterol, is a more effective cholesterol-lowering agent in male, but not as much in female, hamsters, over a feeding period of 90 days.