Decrease In Cholesterol Absorption Research Articles

Ezetimibe and diabetes mellitus:a new strategy for lowering cholesterol

Diabetes mellitus is a well-recognized risk factor for cardiovascular diseases, so an “aggressive” therapeutic approach is necessary for some high-risk patients. Low-density lipoprotein (LDL) cholesterol is the leading modifiable risk factor for the development of atherosclerotic cardiovascular diseases (ACVD). It is known that statins are the gold standard to control LDL cholesterol and reduce the risks associated with ACVD; however, many patients do not achieve their LDL cholesterol target or are unable to use this class of drugs due to associated side effects. Recent studies of non-statin cholesterol-lowering drugs (ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors) have demonstrated benefits in the treatment of ACVD, and new drugs (bempedoic acid, inclisiran) have shown promising results in preclinical and clinical studies. New evidence suggests that prescription of ezetimibe as an addition to statins provides an additional cardioprotective effect. This review aims to discuss the role of ezetimibe in the treatment of patients with diabetes mellitus and dyslipoproteinemia and to consider its efficacy and safety. The combined use of low- or moderate-intensity therapy with statins and ezetimibe involves two complementary mechanisms: a decrease in the intracellular concentration of cholesterol with increased uptake of LDL cholesterol by hepatocytes and a decrease in cholesterol absorption in the intestines. These mechanisms act synergistically and can provide the same overall effect as when using high-intensity statin therapy. The safety of combined therapy is equivalent to that of monotherapy with HMG-CoA reductase inhibitors in similar doses. This combination is generally better tolerated than high doses of HMG-CoA reductase inhibitors and has advantages in patients at risk of myopathy and statin-induced type 2 diabetes. Thus, despite some caveats, ezetimibe remains the drug of choice in the arsenal of pharmacological agents.

Inhibiting Cholesterol Absorption During Lactation Programs Future Intestinal Absorption of Cholesterol in Adult Mice

In nematodes, the intestine senses and integrates early life dietary cues that lead to lifelong epigenetic adaptations to a perceived nutritional environment-it is not clear whether this process occurs in mammals. We aimed to establish a mouse model of reduced dietary cholesterol availability from maternal milk and investigate the consequences of decreased milk cholesterol availability, early in life, on the metabolism of cholesterol in adult mice. We blocked intestinal absorption of cholesterol in milk fed to newborn mice by supplementing the food of dams (for 3 weeks between birth and weaning) with ezetimibe, which is secreted into milk. Ezetimibe interacts with the intestinal cholesterol absorption transporter NPC1l1 to block cholesterol uptake into enterocytes. Characterization of these offspring at 24 weeks of age showed a 27% decrease in cholesterol absorption (P < .001) and reduced levels of Npc1l1 messenger RNA and protein, but not other cholesterol transporters, in the proximal small intestine. We observed increased histone H3K9me3 methylation at positions -423 to -607 of the proximal Npc1l1 promoter in small intestine tissues from 24-week-old offspring fed ezetimibe during lactation, compared with controls. These findings show that the early postnatal mammalian intestine functions as an environmental sensor of nutritional conditions, responding to conditions such as low cholesterol levels by epigenetic modifications of genes. Further studies are needed to determine how decreased sterol absorption for a defined period might activate epigenetic regulators; the findings of our study might have implications for human infant nutrition and understanding and preventing cardiometabolic disease.

Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice.

The objective of this study was to investigate the effect of Lactobacillus acidophilus ATCC 4356 on the development of atherosclerosis in apolipoprotein E-knockout (ApoE(-/-)) mice. Eight-week-old ApoE(-/-) mice were fed a Western diet with or without L. acidophilus ATCC 4356 daily for 16 weeks. L. acidophilus ATCC 4356 protected ApoE(-/-) mice from atherosclerosis by reducing their plasma cholesterol levels from 923 ± 44 to 581 ± 18 mg/dl, likely via a marked decrease in cholesterol absorption caused by modulation of Niemann-Pick C1-like 1 (NPC1L1). In addition, suppression of cholesterol absorption induced reverse cholesterol transport (RCT) in macrophages through the peroxisome proliferator-activated receptor/liver X receptor (PPAR/LXR) pathway. Fecal lactobacillus and bifidobacterium counts were significantly (P < 0.05) higher in the L. acidophilus ATCC 4356 treatment groups than in the control groups. Furthermore, L. acidophilus ATCC 4356 was detected in the rat small intestine, colon, and feces during the feeding trial. The bacterial levels remained high even after the administration of lactic acid bacteria had been stopped for 2 weeks. These results suggest that administration of L. acidophilus ATCC 4356 can protect against atherosclerosis through the inhibition of intestinal cholesterol absorption. Therefore, L. acidophilus ATCC 4356 may be a potential therapeutic material for preventing the progression of atherosclerosis.

Phytosterol stearate esters elicit similar responses on plasma lipids and cholesterol absorption but different responses on fecal neutral sterol excretion and hepatic free cholesterol in male Syrian hamsters

The dietary impact of specific phytosterols incorporated into phytosterol fatty acid esters has not been elucidated. Therefore, we tested the hypothesis that phytosterol esters containing different sterol moieties (sitosterol, sitostanol, or stigmasterol) but the same fatty acid moiety (stearic acid) produce different effects on cholesterol metabolism. Male Syrian hamsters were fed sitosterol, sitostanol, and stigmasterol stearate esters (25 g/kg diet) in an atherogenic diet containing cholesterol (1.2 g/kg) and coconut oil (80 g/kg). The phytosterol stearates produced no decrease in cholesterol absorption or plasma non-high-density lipoprotein cholesterol despite a reduction in liver free cholesterol in hamsters fed both sitosterol and sitostanol stearate diets. In addition, sitosterol stearate significantly increased fecal esterified and total neutral sterol excretion. Stigmasterol stearate did not differ from control in neutral sterol excretion, plasma lipids, or hepatic lipid concentration. Sitosterol stearate demonstrated the highest level of net intestinal hydrolysis, whereas sitostanol and stigmasterol stearate equivalently demonstrated the lowest. The cholesterol-lowering effect in liver-but not plasma-and the limited presence of fecal free sterols indicate that intact (unhydrolyzed) phytosterol stearates may impact cholesterol metabolism by mechanisms unrelated to the role of free phytosterols. The consumption of phytosterol esters at 2.5% of the diet elicited only modest impacts on cholesterol metabolism, although sitosterol stearate had a slightly greater therapeutic impact by lowering liver free cholesterol and increasing esterified and total neutral sterol fecal excretion, possibly due to a greater level of intestinal hydrolysis.

Shaping of the gut microbiota by B lymphocytes influences GATA4-dependent lipid absorption and body fat accumulation (90.8)

Abstract In order to understand the role for B lymphocytes in normal physiology of intestine, we compared global gene expression in the jejunum of wild-type (WT) and B-cell knockout (KO) mice. We found about 300 genes whose expression differed between WT and B-cell KO mice. Genes down-regulated in B- cell KO intestines, were highly enriched for lipid/energy metabolism genes. Consistent with this result, we found lower amounts of para-genital fat and serum leptin level in B-cell KO mice than in their B-cell-sufficient littermates. We revealed GATA4 as the most enriched transcription factor for the down regulated genes. Conditional KO of Gata4 in the intestinal epithelium showed a high correlation with BcKO gene signature. We also found a decrease in cholesterol absorption in the gut of B-cell KO mice (p&amp;lt;0.005) previously observed in Gata4 intestinal KO. In addition, Gata4 KO mice perfectly recapitulated the systemic effects observed in B-cell KO mice presenting decreased levels of body fat and leptin (p&amp;lt;0.01). Studying the mechanism, we found that mice that have B lymphocytes but do not produce soluble antibodies exhibit a very similar gene expression profile as the B-cell KO mice implying that this phenomenon is antibody-dependent. Under germ-free conditions, we found almost no difference between B-cell KO and control mice. Thus we conclude that B lymphocytes are involved in the control of GATA4-dependent lipid absorption and accumulation of body fat by shaping the gut microflora.

Cholesterol absorption decreases after Roux-en-Y gastric bypass but not after gastric banding

The differences in cholesterol metabolism after the 2 most common forms of obesity surgery, Roux-en-Y gastric bypass (RYGB) and gastric banding (GB), have not been well characterized. In this study, effects of RYGB and GB on cholesterol absorption and synthesis were investigated. To this aim, 1-year follow-up of cholesterol metabolism in 2 nonrandomized cohorts undergoing either RYGB (n = 29; age, 45.2 ± 7.7 years; body mass index [BMI], 46.0 ± 6.1 kg/m 2) or GB (n = 26; age, 45.9 ± 8.6 years; BMI, 50.1 ± 7.7 kg/m 2) was performed in a university hospital center specializing in the treatment of morbid obesity. Serum markers of cholesterol synthesis (cholestenol, desmosterol, and lathosterol) and cholesterol absorption (campesterol, sitosterol, avenasterol, and cholestanol) were measured preoperatively and at follow-up and expressed as ratios to cholesterol. As expected based on observed weight loss (25% after RYGB and 17% after GB, P < .001 between groups), both operations decreased serum levels of cholesterol synthesis markers by 12% to 28% (all Ps < .001). A decrease in cholesterol absorption markers was only observed after RYGB (−26% for sitosterol) and not after GB (+16%, P = 2 × 10 −6 for difference between the groups). The difference in sitosterol ratio between the groups remained significant after adjustment for age, BMI, fasting insulin levels, and nutritional status ( P = 2 × 10 −4), indicating a specific effect related to RYGB. We conclude that decrease in cholesterol absorption is a novel beneficial effect of RYGB. Together with an improved control of blood glucose, this may contribute to a better cardiovascular risk profile after RYGB.

Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect

Human treatment with ezetimibe results in a moderate 50% to 54% decrease in cholesterol absorption and a 15% to 20% decrease in plasma LDL-cholesterol levels; nevertheless, the efficacy of ezetimibe therapy has been recently challenged by the ENHANCE trial. We examined the efficacy of a moderate decrease in cholesterol absorption in preventing atherosclerosis formation in the mouse. Congenic 14DKK animals, consisting of a castaneus (CASA/Rk) chromosome 14 interval introgressed onto the C57BL/6J background, displayed a moderate decrease in cholesterol absorption rates. The effect of moderately decreased absorption on atherosclerosis formation was determined in 14DKK apolipoprotein E knockouts (14DKK-apoEKO). When compared to chow diet-fed control apoEKO mice, congenic 14DKK-apoEKO displayed a moderate 41% decrease in cholesterol absorption rates, 30% to 37% decrease in plasma cholesterol levels, and a 70% decrease in atherosclerosis formation. Studies on cholesterol efflux and reverse cholesterol transport (RCT) from 14DKK bone marrow-derived macrophages rejected a 14DKK interval-dependent atheroprotective effects that operate in macrophages. In contrast, 14DKK-apoEKO congenics were characterized by a 60% increase in RCT from peripheral tissue macrophages. These studies strongly suggest that moderately decreased cholesterol absorption rates result in a large atheroprotective effect attributable to a decrease in plasma cholesterol levels and an increase in RCT from peripheral tissue macrophages.

Decreased Expression of Cholesterol 7α-Hydroxylase and Altered Bile Acid Metabolism in Apobec-1−/− Mice Lead to Increased Gallstone Susceptibility

Quantitative trait mapping in mice identified a susceptibility locus for gallstones (Lith6) spanning the Apobec-1 locus, the structural gene encoding the RNA-specific cytidine deaminase responsible for production of apolipoprotein B48 in mammalian small intestine and rodent liver. This observation prompted us to compare dietary gallstone susceptibility in Apobec-1(-/-) mice and congenic C57BL/6 wild type controls. When fed a lithogenic diet (LD) for 2 weeks, 90% Apobec-1(-/-) mice developed solid gallstones in comparison with 16% wild type controls. LD-fed Apobec-1(-/-) mice demonstrated increased biliary cholesterol secretion as well as increased cholesterol saturation and bile acid hydrophobicity indices. These changes occurred despite a relative decrease in cholesterol absorption in LD-fed Apobec-1(-/-) mice. Among the possible mechanisms to account for this phenotype, expression of Cyp7a1 mRNA and protein were significantly decreased in chow-fed Apobec-1(-/-) mice, decreasing further in LD-fed animals. Cyp7a1 transcription in hepatocyte nuclei, however, was unchanged in Apobec-1(-/-) mice, excluding transcriptional repression as a potential mechanism for decreased Cyp7a1 expression. We demonstrated that APOBEC-1 binds to AU-rich regions of the 3'-untranslated region of the Cyp7a1 transcript, containing the UUUN(A/U)U consensus motif, using both UV cross-linking to recombinant APOBEC-1 and in vivo RNA co-immunoprecipitation. In vivo Apobec-1-dependent modulation of Cyp7a1 expression was further confirmed following adenovirus-Apobec-1 administration to chow-fed Apobec-1(-/-) mice, which rescued Cyp7a1 gene expression. Taken together, the findings suggest that the AU-rich RNA binding-protein Apobec-1 mediates post-transcriptional regulation of murine Cyp7a1 expression and influences susceptibility to diet-induced gallstone formation.

Sunflower Protein Hydrolysates Reduce Cholesterol Micellar Solubility

Plant protein hydrolysates are a source of bioactive peptides. There are peptides that decrease the micellar cholesterol solubility from bile acids and therefore may reduce in vivo cholesterol absorption. The presence of these peptides in sunflower protein hydrolysates has been studied. Sunflower protein hydrolysates produced with alcalase plus flavourzyme or with pepsin plus pancreatin inhibited in some degree the cholesterol incorporation to micelles. Protein hydrolysates generated after 30 min of hydrolysis with alcalase, and after 30 min of hydrolysis with pepsin, were the inhibitoriest of the cholesterol incorporation to micelles. The average amino acid hydrophobicity of inhibitory peptides in cholesterol micelles was higher than the observed in the corresponding protein hydrolysates. This high hydrophobicity probably favours their inclusion in the lipid micelles. In vivo, this inhibition may translate in a decrease of cholesterol absorption. Reported results show that a combination of different characteristics such as peptide size or hydrophobicity may be responsible of the inhibitory activity of generated peptides.

Corn fiber oil and sitostanol decrease cholesterol absorption independently of intestinal sterol transporters in hamsters

Objective The aim of this study was to investigate the cholesterol-lowering mechanisms of corn fiber oil (CFO), ferulate phytostanyl esters (FPEs) and parent compounds of FPE, including sitostanol and ferulic acid, in hamsters. Method Seventy male Golden Syrian hamsters were randomly assigned to six experimental diets for 4 weeks: (1) cornstarch–casein–sucrose-based control diet (control); and (2) control diet plus 0.1% (wt/wt) cholesterol (cholesterol–control). The remaining four groups were given cholesterol–control diet with: (3) 10% (wt/wt) CFO; (4) 0.5% (wt/wt) sitostanol; (5) 0.23% (wt/wt) ferulic acid; and (6) 0.73% (wt/wt) FPE. At the end of dietary intervention, total plasma cholesterol, high-density lipoprotein cholesterol and triglyceride concentrations were determined. Parameters of cholesterol kinetics, including cholesterol absorption and synthesis, as well as mRNA expression of sterol transporters such as Niemann–Pick C1 like 1 (NPC1L1), ATP-binding cassette G5 (ABCG5) and ABCG8, were assessed. Results Supplementation with CFO decreased ( P<.0001) plasma total cholesterol levels by 29% as compared with the cholesterol–control group, while FPE and sitostanol reduced ( P<.02) cholesterolemia by 15% and 14%, respectively. CFO and sitostanol decreased ( P<.05) cholesterol absorption by 24% compared to the cholesterol–control group. Dietary intervention did not alter the intestinal gene expression of ABCG5, ABCG8 and NPC1L1. Conclusion The present results show that the CFO-induced and sitostanol-induced decrease in cholesterol absorption is independent of intestinal enterocyte sterol transporters such as ABCG5, ABCG8 and NPC1L1 in hamsters.

Both free and esterified plant sterols reduce cholesterol absorption and the bioavailability of β-carotene and α-tocopherol in normocholesterolemic humans

Plant sterols reduce cholesterol absorption, which leads to a decrease in plasma and LDL-cholesterol concentrations. Plant sterols also lower plasma concentrations of carotenoids and alpha-tocopherol, but the mechanism of action is not yet understood. The aims of this clinical study were to determine whether plant sterols affect the bioavailability of beta-carotene and alpha-tocopherol in normocholesterolemic men and to compare the effects of plant sterol esters and plant free sterols on cholesterol absorption. Twenty-six normocholesterolemic men completed the double-blind, randomized, crossover study. Subjects consumed daily, for 1 wk, each of the following 3 supplements: a low-fat milk-based beverage alone (control) or the same beverage supplemented with 2.2 g plant sterol equivalents provided as either free sterols or sterol esters. During this 1-wk supplementation period, subjects consumed a standardized diet. Both of the milks enriched with plant sterols induced a similar (60%) decrease in cholesterol absorption. Plant free sterols and plant sterol esters reduced the bioavailability of beta-carotene by approximately 50% and that of alpha-tocopherol by approximately 20%. The reduction in beta-carotene bioavailability was significantly less with plant free sterols than with plant sterol esters. At the limit of significance (P = 0.054) in the area under the curve, the reduction in alpha-tocopherol bioavailability was also less with plant free sterols than with plant sterol esters. Both plant sterols reduced beta-carotene and alpha-tocopherol bioavailability and cholesterol absorption in normocholesterolemic men. However, plant sterol esters reduced the bioavailability of beta-carotene and alpha-tocopherol more than did plant free sterols.

Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men

Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin (r = 0.36-0.46, P < 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r = -0.37-0.40, P < 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU (P < 0.05). Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for. We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism.

Increased intestinal ABCA1 expression contributes to the decrease in cholesterol absorption after plant stanol consumption

Increased intestinal ABCA1 expression contributes to the decrease in cholesterol absorption after plant stanol consumption

Increased intestinal ABCA1 expression contributes to the decrease in cholesterol absorption after plant stanol consumption.

The hypocholesterolemic effect of plant stanols is explained by a decreased intestinal cholesterol absorption due to a competition between plant stanols and cholesterol for incorporation into mixed micelles. Earlier we had suggested that plant stanols have a so far unknown action inside the enterocytes. The recent discovery of the involvement of ATP binding cassette (ABC) transporters in cholesterol absorption was a lead to further explore the hypocholesterolemic mechanism of plant stanols. We found that mixed micelles enriched with sitostanol or with cholesterol plus sitostanol were potent inducers of ABCA1 expression in caco-2 cells, an accepted model to study human intestinal lipoprotein metabolism. Based on these findings, we now hypothesize that plant stanols--and possibly plant sterols--increase ABCA1-mediated cholesterol efflux back into the intestinal lumen. We further hypothesize that intracellular levels of plant stanols are monitored by the same sensors (SREBP-2 and LXR) as those that monitor cholesterol. Consequently, increased plant stanol levels within the enterocyte activate cholesterol efflux through ABCA1- but not SREBP-2-mediated endogenous cholesterol synthesis even if intracellular cholesterol concentrations are lowered through consumption of plant stanols. If our hypothesis is correct, then the LXR pathway may be a target for dietary regulation of intestinal lipid metabolism.

ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism

Members of the family of ABC transporters are involved in different processes of sterol metabolism, and ABCA1 was recently identified as a key regulator of high-density lipoprotein (HDL) metabolism. Our aim was to further analyze the role of ABCA1 in cholesterol metabolism. ABCA1-deficient mice (ABCA1-/-) and wild-type mice were compared for different aspects of sterol metabolism. Intestinal cholesterol absorption was determined by a dual stable isotope technique, and analysis of fecal, plasma, and tissue sterols was performed by gas chromatography/mass spectrometry. Key regulators of sterol metabolism were investigated by Northern and Western blot analyses or enzyme activity assays. ABCA1-disrupted sv129/C57BL/6 hybrid mice showed a significant reduction in intestinal cholesterol absorption. The decrease in cholesterol absorption was followed by an enhanced fecal loss of neutral sterols, whereas fecal bile acid excretion was not affected. Total body cholesterol synthesis was significantly increased, with enhanced 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase observed in adrenals and spleen. In addition, ABCA1-/- mice showed markedly increased concentrations of cholesterol precursors in the plasma, lung, intestine, and feces. Reduced HMG-CoA reductase messenger RNA and enzyme activity in the liver suggest that enhanced cholesterol synthesis in ABCA1-/- mice occurs in peripheral tissues rather than the liver. The metabolism of cholesterol and cholesterol precursors is markedly affected by a lack of ABCA1 function.

Pharmacological properties of YM17E, an acyl-CoA:cholesterol acyltransferase inhibitor, and diarrheal effect in beagle dogs.

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]ben zene dihydrochloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high-density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholesterolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secretory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment

Cholesterol absorption and metabolism and LDL and HDL kinetics were investigated in 11 hypercholesterolaemic non-insulin-dependent diabetic men off and on a hypolipidaemic treatment with sitostanol ester, (3 g sitostanol daily) dissolved in rapeseed oil margarine, by a double-blind crossover study design. Serum total, VLDL and LDL cholesterol and apoprotein B fell significantly by 6 +/- 2, 12 +/- 6, 9 +/- 3 and 6 +/- 2%, mean +/- SEM, and HDL cholesterol was increased by 11 +/- 4% (p < 0.05) by sitostanol ester. LDL cholesterol and apoprotein B were significantly decreased in the dense (1.037-1.055 g/ml), but not light, LDL subfraction due to a significantly diminished transport rate for LDL apoprotein B, while the fractional catabolic rate was unchanged. HDL kinetics, measured with autologous apoprotein A I, was unaffected by sitostanol ester. Cholesterol absorption efficiency was markedly reduced from 25 +/- 2 to 9 +/- 2% (p < 0.001) during sitostanol ester followed by proportionately decreased serum plant sterol proportions. Cholesterol precursor sterol proportions in serum, fecal neutral sterol excretion, and cholesterol synthesis, cholesterol transport, and biliary secretion were all significantly increased by sitostanol ester. We conclude that the sitostanol ester-induced decrease in cholesterol absorption compensatorily stimulated cholesterol synthesis, had no effect on fractional catabolic rate, but decreased transport rate for LDL apoprotein B so that serum total, VLDL and LDL cholesterol levels were decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment

Cholesterol absorption and metabolism and LDL and HDL kinetics were investigated in 11 hypercholesterolaemic non-insulin-dependent diabetic men off and on a hypolipidaemic treatment with sitostanol ester, (3 g sitostanol daily) dissolved in rapeseed oil margarine, by a double-blind crossover study design. Serum total, VLDL and LDL cholesterol and apoprotein B fell significantly by 6±2, 12±6, 9±3 and 6±2%, mean ±SEM, and HDL cholesterol was increased by 11±4% (p<0.05) by sitostanol ester. LDL cholesterol and apoprotein B were significantly decreased in the dense (1.037–1.055 g/ml), but not light, LDL subfraction due to a significantly diminished transport rate for LDL apoprotein B, while the fractional catabolic rate was unchanged. HDL kinetics, measured with autologous apoprotein AI, was unaffected by sitostanol ester. Cholesterol absorption efficiency was markedly reduced from 25±2 to 9±2% (p<0.001) during sitostanol ester followed by proportionately decreased serum plant sterol proportions. Cholesterol precursor sterol proportions in serum, fecal neutral sterol excretion, and cholesterol synthesis, cholesterol transport, and biliary secretion were all significantly increased by sitostanol ester. We conclude that the sitostanol ester-induced decrease in cholesterol absorption compensatorily stimulated cholesterol synthesis, had no effect on fractional catabolic rate, but decreased transport rate for LDL apoprotein B so that serum total, VLDL and LDL cholesterol levels were decreased. Dietary rapeseed oil margarine rich in sitostanol ester was well tolerated, appears to be safe from the nutritional point of view and effective for lowering VLDL and LDL cholesterol and increasing HDL cholesterol in hypercholesterolaemic non-insulin-dependent diabetic subjects.

Dietary -sitostanol related to absorption, synthesis and serum level of cholesterol in different apolipoprotein E phenotypes

Effects of small amounts of sitosterol, sitostanol and sitostanol esters ( < 1 g/day of free sterols) dissolved in rapeseed oil (RSO) were studied on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and different apolipoprotein E phenotypes on an RSO diet. One of the four groups was an RSO-fed control. Serum total and LDL cholesterol reductions were small in different plant sterol-fed groups, tended to be highest in the sitostanol ester group (−7%), but were significantly reduced by about 5% in the combined plant sterol groups. The reductions were −8% in the subjects with E4 allele and insignificant in those with apo E3/3 phenotype. Cholesterol precursor sterols in serum, markers of cholesterol synthesis, were increased only in the subjects with ϵ4 allele. Cholesterol absorption was reduced by 7%, being 31% in the subjects with ϵ4 allele, and fecal elimination of cholesterol was increased, a finding also indicating increased cholesterol synthesis. The changes in cholesterol absorption were related to those in fecal plant sterols (change in dietary intake) and serum total and LDL cholesterol ( P=0.04, 0.01 and 0.05, respectively). Thus, small amounts of dietary plant sterols ( < 1 g/day), especially sitostanol esters dissolved in dietary fats, decrease serum total and LDL cholesterol by a proportional decrease in cholesterol absorption which, in turn, is associated with a compensatory increase in cholesterol synthesis. The effects are most consistent in subjects with E4 allele, but for effective hypocholesterolemic treatment dietary amount of sitostanol ester should exceed 1 g/day.

Optimizing the effect of plant sterols on cholesterol absorption in man

During three experimental periods, nine adults were hospitalized on a metabolic ward and fed a meal containing 500 mg of cholesterol as a component of scrambled eggs. In addition, the meal contained: 1) no additive, 2) 1 g beta-sitosterol, or 3) 2 g beta-sitosteryl oleate. Stools for the succeeding 5 days were analyzed to determine the percentage of the cholesterol in the test meal that was absorbed. The addition of beta-sitosterol resulted in a 42% decrease in cholesterol absorption; the beta-sitosteryl oleate caused a 33% reduction. These results indicate that the judicious addition of beta-sitosterol or beta-sitosteryl oleate to meals containing cholesterol-rich foods will result in a significant decrease in cholesterol absorption, with a consequent decrease in plasma cholesterol.