Reduced Cholesterol Concentrations Research Articles

Adenoviral low density lipoprotein receptor attenuates progression of atherosclerosis and decreases tissue cholesterol levels in a murine model of familial hypercholesterolemia

Familial hypercholesterolemia is an autosomal codominant disease characterized by high concentrations of pro-atherogenic lipoproteins and premature atherosclerosis secondary to low density lipoprotein receptor (LDLr) deficiency. In the current study, the effects of gene transfer with 5 × 10 10 particles of E1E3E4-deleted adenoviral vectors expressing the LDLr (AdLDLr) or VLDLr (AdVLDLr) under control of the hepatocyte-specific human α 1 -antitrypsin promoter and 4 copies of the human apo E enhancer in C57BL/6 LDLr −/− mice were investigated. Evaluation was performed in both sexes and in mice fed either standard chow or an atherogenic diet containing 0.2% cholesterol and 10% coconut oil. Compared to control mice, AdLDLr and AdVLDLr persistently decreased plasma non-HDL cholesterol in both sexes and on both diets. Six months after LDLr gene transfer in mice fed the atherogenic diet, average intimal area was 2.5-fold ( p < 0.01) and 3.2-fold ( p < 0.001) lower in male and female mice, respectively, compared to controls. In mice fed standard chow, intimal area was reduced 22-fold ( p < 0.001) and 21-fold ( p < 0.001) after LDLr gene transfer in male and female mice, respectively. We show that non-HDL lipoproteins are more atherogenic in female mice, independent of sex differences of plasma HDL cholesterol levels, and that saturated fat does not have an effect on atherosclerosis independent of plasma cholesterol levels. Finally, quantification of tissue cholesterol levels indicates that AdLDLr does not induce cholesterol accumulation in the liver and reduces cholesterol content in the myocardium, quadriceps muscle and kidney. In conclusion, hepatocyte-specific LDLr gene transfer significantly improves cholesterol homeostasis in LDLr −/− mice.

Phytosterols and pectin added to a high‐saturated fat diet do not show hypocholesterolemic activity in female guinea pigs

AbstractThis paper presents the results of a study whose aim was to test the effects of several doses of pectin and phytosterols on the sterol content in plasma, liver and feces of guinea pigs, when added to a high‐saturated fat diet. The treatments followed a 3×3 factorial design, with three levels of pectin (0, 3.67 and 6.93%) and three levels of phytosterols (0, 1.37 and 2.45%). Seventy‐two female Dunkin Hartley guinea pigs were randomly assigned to the treatment groups (eight animals per group). The duration of the treatment was 4 weeks. No differences were found in plasma cholesterol concentrations, while in liver we saw a reduction in cholesterol concentration after phytosterol feeding. Moreover, we found no pectin effects. Plant sterol concentration increased in plasma and liver after phytosterol ingestion, with the highest concentrations being obtained with the intermediate pectin dose. Our results suggest that a high‐saturated diet may impair the cholesterol‐lowering properties of plant sterols and pectin.

'Real-life' reduction in cholesterol with statins, 1993 to 2002.

AIMSTo evaluate the impact of lipid-lowering treatment on cholesterol concentrations in the setting of normal care.METHODSThis was a retrospective review of all cholesterol measurements made in Tayside, Scotland, between 1993 and 2002, linked to dispensed prescribing data for lipid-lowering drugs. It was conducted in the setting of normal care and included all patients who underwent cholesterol measurement. The main outcome measure was cholesterol concentration.RESULTSA total of 401 489 cholesterol measurements were made on 128 240 patients over the study period. Measurements were categorized as treated and untreated according to whether patients were exposed to lipid-lowering treatment at the time the total cholesterol concentration was measured. Those categorized as untreated fell by 0.86 mmol l−1 (13.9%) and those categorized as treated by 1.45 mmol l−1 (23.5%). The difference between baseline and follow-up cholesterol concentrations in intention-to-treat patients was 1.53 mmol l−1 (24%) in 2002. In the same year, mean cholesterol concentration was 4.71 mmol l−1 (a fall of 1.65 mmol l−1 or 25.9%) in patients judged to be taking their lipid-lowering medication, compared with 5.20 mmol l−1 (a fall of 1.16 mmol l−1 or 18.2%) in those judged not to be taking treatment. Cholesterol fell by 0.38 mmol l−1 (6.3%) in a cohort of never treated patients (n = 33 679) between 1993 and 2002.CONCLUSIONSThe impact of lipid-lowering drugs on population cholesterol concentrations in the setting of normal care was significant and comparable with the cholesterol reductions seen in the setting of major statin trials, despite a significant proportion of the population receiving low dose treatment. In those subjects judged to be taking their medication, the benefits achieved were substantial. The impact of nondrug factors is indicated by the fall in population cholesterol seen in the absence of lipid-lowering treatment.WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Statins reduce cholesterol concentrations and cardiovascular events in randomized clinical trials.Much less is known about their impact in the setting of normal care.WHAT THIS STUDY ADDS This is the first study to assess the effectiveness of lipid-lowering treatment in the general population.We have also estimated the resultant impact on major vascular events.We have examined the actual and potential impact of lipid-lowering treatment.

Efficacy of plant sterols is not influenced by dietary cholesterol intake in hypercholesterolemic individuals

Plant sterols (PSs) reduce plasma total and low-density lipoprotein cholesterol (LDL-C) levels by reducing cholesterol absorption; however, it is not known whether the level of dietary cholesterol intake has an impact on the efficacy of PSs on blood lipids. The purpose of this study was to determine the effect of high vs low dietary cholesterol levels on the lipid-lowering efficacy of free PSs. The study was a semirandomized, double-blind, crossover trial consisting of four 28-day feeding phases each separated by a 4-week washout period. Otherwise healthy hypercholesterolemic subjects (n = 22) consumed each of ( a) low-cholesterol control (C −S −), ( b) high-cholesterol control (C +S −), ( c) 22 mg PSs per kilogram of body weight with a low-cholesterol diet (C −S +), and ( d) 22 mg PSs per kilogram of body weight with a high-cholesterol diet (C +S +). Blood was drawn on the first and last 2 days of each phase to measure plasma total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triacylglycerols as well as plasma campesterol and β-sitosterol concentrations. Dietary cholesterol had no effect on PS efficacy as a cholesterol-lowering agent because no interaction was found between the 2 factors. However, dietary cholesterol and PS intake had significant independent effects on plasma total cholesterol, LDL-C, and high-density lipoprotein cholesterol levels. β-Sitosterol levels in plasma increased ( P < .0001) as a result of PS supplementation. Data from the present study indicate that, although PSs and dietary cholesterol exert independent effects on plasma cholesterol, PS efficacy is not affected by varying levels of cholesterol intake.

Thermally Oxidized Oil Increases the Expression of Insulin-Induced Genes and Inhibits Activation of Sterol Regulatory Element-Binding Protein-2 in Rat Liver

Administration of oxidized oils to rats or pigs causes a reduction of their cholesterol concentrations in liver and plasma. The reason for this effect is unknown. We tested the hypothesis that oxidized oils lower cholesterol concentrations by inhibiting the proteolytic activation of sterol regulatory element-binding protein (SREBP)-2 in the liver and transcription of its target genes involved in cholesterol synthesis and uptake through an upregulation of gene expression of insulin-induced genes (Insig). For 6 d, 18 rats were orally administered either sunflower oil (control group) or an oxidized oil prepared by heating sunflower oil. Rats administered the oxidized oil had higher messenger RNA (mRNA) concentrations of acyl-CoA oxidase and cytochrome P450 4A1 in the liver than control rats (P < 0.05), indicative of activation of PPARα. Furthermore, rats administered the oxidized oil had higher mRNA concentrations of Insig-1 and Insig-2a, a lower concentration of the mature SREBP-2 in the nucleus, lower mRNA concentrations of the SREBP-2 target genes 3-hydroxy-3-methylglutaryl CoA reductase and LDL receptor in their livers, and a lower concentration of cholesterol in liver, plasma, VLDL, and HDL than control rats (P < 0.05). In conclusion, this study shows that reduced cholesterol concentrations in liver and plasma of rats administered an oxidized oil were due to an inhibition of the activation of SREBP-2 by an upregulation of Insig, which in turn inhibited transcription of proteins involved in hepatic cholesterol synthesis and uptake.

Phytosterols: natural compounds with established and emerging health benefits

Phytosterols (plant sterols and stanols) are naturally occurring compounds which are found in all foods of plant origin. The term phytosterols refers to more than 200 different compounds. The most abundant ones in the human diet are sitosterol and campesterol. Their saturated counterparts, sitostanol and campestanol, are found in much lower amounts. Good food sources of phytosterols include vegetable oils, cereal grains, nuts, legumes, and fruits and vegetables. Phytosterols are structurally similar to cholesterol. Despite this structural similarity, they are not absorbed in significant quantities. Absorption is less than 2% for phytosterols, while it is 30-60% for cholesterol. Phytosterols are known to have various bioactive properties, which may have an impact on human health, and as such boosted interest in phytosterols in the past decade. The most important benefit is their blood cholesterol-lowering effect via partial inhibition of intestinal cholesterol absorption. The recommended daily intake of 2 g of phytosterols reduces cholesterol absorption by 30-40% and LDL-cholesterol by 10% on average. Other claimed benefits of phytosterols are possible anti-atherogenic effects as well as, particularly for beta-sitosterol, immune stimulating and anti-inflammatory activities. Furthermore, there is emerging evidence suggesting that particularly plant sterols may have beneficial effects against the development of different types of cancers, like colorectal, breast and prostate cancers. It is not clear whether mechanisms other than the established cholesterol-lowering action of phytosterols as such also contribute to these potential health benefits.

Effect of Dietary Rhodobacter capsulatus on Cholesterol Concentration and Fatty Acid Composition in Broiler Meat

The study was designed to investigate the effects of dietary Rhodobacter capsulatus on cholesterol concentration and fatty acid composition in broiler meat. A total of 45 two-week-old male broiler chicks were randomly assigned into 3 treatment groups and fed ad libitum diets supplemented with 0 (control), 0.02, and 0.04% R. capsulatus for a 6-wk feeding period. The results of this study revealed that the supplementation of 0.04% R. capsulatus in diet reduced (P < 0.05) cholesterol and triglyceride concentrations in broiler meat. The concentrations (expressed as a percentage of total fatty acids) of oleic acid (18:1), linoleic acid (18:2), and linolenic (18:3) acid in thigh muscle and breast muscle were higher (P < 0.05) in the broilers fed the 0.04% R. capsulatus supplemented diet than in the broilers fed the control diet. The ratio of unsaturated fatty acids to saturated fatty acids was greater (P < 0.05) in both muscles of broilers fed the 0.04% R. capsulatus supplemented diet than the control diet. In addition, the concentrations of serum cholesterol and triglyceride, and hepatic cholesterol and triglyceride were also reduced (P < 0.05) by dietary R. capsulatus. Compared with the control diet, the 0.04% R. capsulatus supplemented diet reduced (P < 0.05) the ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol. Moreover, the supplementation of R. capsulatus in broiler diets did not show any adverse effect on production performance. Therefore, these results conclude that the application of R. capsulatus into diet may be feasible to reduce cholesterol concentration and improve the ratio of unsaturated fatty acids to saturated fatty acids in broiler meat.

DIETARY GANGLIOSIDE INHIBITS ACUTE INFLAMMATORY SIGNALS IN INTESTINAL MUCOSA AND BLOOD INDUCED BY SYSTEMIC INFLAMMATION OF ESCHERICHIA COLI LIPOPOLYSACCHARIDE

Our previous study demonstrated that feeding ganglioside increased total ganglioside content while decreasing cholesterol and caveolin-1 content in developing rat intestinal lipid microdomains. Cholesterol or caveolin depletion in membranes inhibits inflammatory signaling by disrupting microdomain structure. We hypothesized that dietary ganglioside-induced reduction in cholesterol content will reduce proinflammatory mediators in the intestinal mucosa after acute exposure to bacterial endotoxin. Weanling rats were fed semipurified diets with 0.1% (wt/wt of total fat) gangliosides (treatment) or without ganglioside (control). After 2 weeks of feeding, half of animals from each diet group were injected with saline or lipopolysaccharide (LPS) endotoxin (Escherichia coli serotype O111:B4, intraperitoneal, 3 mg/kg body weight) to induce acute gut inflammation. Intestinal mucosa and blood were collected after 6 h. The effect of dietary ganglioside on proinflammatory mediators including cholesterol, platelet-activating factor, prostaglandin E2, leukotriene B4 (LTB4), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) was determined in inflamed mucosa and blood. Feeding animals the control diet increased cholesterol content in intestinal lipid microdomains by 92% after LPS injection compared with saline injection. Animals fed the ganglioside diet significantly decreased cholesterol content in lipid microdomains by 60% compared with animals fed the control diet. Feeding animals the ganglioside diet increased total ganglioside content by 90% while decreasing platelet-activating factor content by 45% in the inflamed mucosa by acute systemic exposure to LPS compared with animals fed the control diet. When animals were fed the ganglioside diet, the levels of prostaglandin E2, LTB4, IL-1beta, and TNF-alpha were lower in inflamed mucosa, and LTB4, IL-1beta, and TNF-alpha were decreased in plasma by 41%, 58%, and 55% compared with control animals, respectively. The present study demonstrates that dietary gangliosides inhibit proinflammatory signals in the intestine and blood induced by acute inflammation of LPS and suggests therapeutic potential in the treatment and management of acute local and systemic inflammatory diseases.

Quality parameters of noodles made with various supplements

The influence of various supplements (extruded maize, maize, defatted soy flour and maize/soy flour blends, lecithin and wheat straw) on the pasta quality has been examined. Noodles were prepared by means of conventional laboratory equipment. Common wheat flour supplemented with 1% lecithin powder, 20% extruded maize flour, 20% maize flour, 10% defatted soy flour, 20% defatted soy and maize flour blend (1:1), and 7.5% wheat straw was used. The produced pasta was dried at 55&amp;grad;C in a laboratory dryer (Instrumentaria, Croatia) to 13.0% moisture. Pasta colour was evaluated with fresh pasta by measuring L*, a*, b* parameters by means of a reflectance colorimeter (CR 300 Chroma-metter, Minolta, Japan). The following parameters of cooked noodles were determined: volume increase coefficient, water uptake (g/g), optimum cooking time (min), and cooking loss (%). Sensory quality was evaluated on a scale of 1&amp;minus;5 for: odour, external appearance, flavour and mouth feel, and total quality scores. The noodles made with extruded maize flour, maize flour, and wheat straw supplements had the highest total sensory score. Cooking losses of these samples were below 10%. Regardless of the fact that the sample with lecithin had the lowest cooking loss, it was not acceptable for the panel members. Supplementation with extruded maize, maize and defatted soy flours, and wheat straw could be used to produce pasta without eggs, with a reduced cholesterol content, enriched with dietary fibre and possessing a lower glycemic index.

A Green Tea Catechin Extract Upregulates the Hepatic Low‐Density Lipoprotein Receptor in Rats

Green tea extracts have hypocholesterolaemic properties in epidemiological and animal intervention studies. Upregulation of the low-density lipoprotein (LDL) receptor may be one mechanism to explain this as it is the main way cholesterol is removed from the circulation. This study aimed to determine if a green tea extract could upregulate the hepatic LDL receptor in vivo in the rat. A green tea extract (GTE) enriched in its anti-oxidant constituents, the catechins, was fed to rats (n = 6) at concentrations of either 0, 0.5, 1.0 or 2.0% (w/w) mixed in with their normal chow along with 0.25% (w/w) cholesterol for 12 days. Administration of the GTE had no effect on plasma total or LDL cholesterol concentrations but high-density lipoprotein significantly increased (41%; p < 0.05). Interestingly, there was a significant increase in LDL receptor binding activity (2.7-fold) and LDL receptor protein (3.4-fold) in the 2% (w/w) treatment group compared to controls. There were also significant reductions in liver total and unesterified cholesterol (40%). Administration of the GTE significantly reduced cholesterol absorption (24%) but did not affect cholesterol synthesis. These results show that, despite no effect on plasma cholesterol, the GTE upregulated the LDL receptor in vivo. This appears to be via a reduction in liver cholesterol concentration and suggests that the green tea extract was able to increase the efflux of cholesterol from liver cells.

Cholesterol-Lowering Effect of Ezetimibe in Uridine Diphosphate Glucuronosyltransferase 1A-Deficient (Gunn) Rats

Ezetimibe (EZE) selectively blocks intestinal cholesterol absorption by interacting with Niemann-Pick C1 Like 1 (NPC1L1). After administration, EZE is extensively metabolized in liver and intestine to its phenolic glucuronide form (EZE-G) by uridine diphosphate glucuronosyltransferases (UGTs), among which UGT1A1 and 1A3 exhibit highest activity. EZE-G is excreted into bile and undergoes extensive enterohepatic recirculation. Considering the pharmacokinetic properties of EZE and an in vitro binding study showing the high affinity binding of EZE-G to NPC1L1, glucuronidation by UGTs has been believed to be essential for the pharmacological efficacy of EZE. To study the role of glucuronidation by UGTs for the cholesterol-lowering effect of EZE, in vitro and in vivo studies were performed using Gunn rats, which hereditarily lack the expression of UGT1A enzymes. The biliary excreted amount of EZE-G was reduced by 73% up to 3 h after administration of EZE (0.3 mg/kg) in Gunn rats, which is consistent with the reduction of in vitro EZE glucuronidation activity found in liver and intestinal microsome from Gunn rats. These results indicate that the formation of EZE-G in Gunn rats is much lower than that in Wistar rats. However, in vivo study showed that 0.3 mg/kg EZE, which is the clinically relevant dose, reduced cholesterol absorption in both Wistar and Gunn rats to nearly the same degree and the dose dependence was not significantly different between Wistar and Gunn rats at the range 0.001 approximately 0.3 mg/kg. These results indicate that a deficiency of UGT1A activity does not necessarily alter the cholesterol-lowering effect of EZE in rats at therapeutic doses.

Cholesterol-lowering properties of plant sterols esterified with beef tallow fatty acids in hamsters

Abstract Plant sterol esters (PSE) reduce plasma low-density lipoprotein cholesterol concentration by inhibiting cholesterol absorption. Previous work in our laboratory indicated that PSE containing stearic acid (SA), compared to linoleic acid, were significantly more effective at reducing cholesterol absorption. We tested the cholesterol lowering properties of PSE containing fatty acids from beef tallow, a natural and abundant source of SA. Male hamsters were fed diets containing 0.0%, 0.5%, 1.0%, or 5.0% beef tallow PSE for 4 weeks. Dose-dependent reductions ( P P

Occurrence and Biological Properties of Sphingolipids - A Review

Sphingolipids are a complex group of polar lipids. Variations in their components (backbone, polar head group and fatty acid) engenders a large and complex structural variety which affects the biological properties of the individual molecules. Sphingolipids are omnipresent in foodstuffs, can cross the intestinal barrier and are biologically active. The quantities in food range from a few μg/kg in fruits and some vegetables up to 1 g/kg in milk products, eggs, meat and soybeans. Several positive impacts of sphingolipids on human health have been described: In vitro experiments measuring the antibacterial properties of sphingolipids have been successfully carried out. A sphingolipid-enriched diet showed inhibitory effects on the formation of early colon carcinoma precursors (Aberrant Crypt Foci (ACF)) in mice. Sphingolipid metabolites also induce apoptosis in transformed human cell cultures. Taken together, there is a high probability that sphingolipids have anticancerogenic properties in humans. Finally, a specific group of sphingolipids is essential for the maintenance of nerve function and structure and the enrichment of sphingomyelin in a cholesterol-rich diet successfully reduces cholesterol absorption. Although sphingolipids are probably not essential dietary components, they can significantly contribute to human health. Keywords: Sphingolipids, sphingomyelin, human nutrition, biological activity, cholesterol, cancer

Effect of Dietary Fish Meal on Production Performance and Cholesterol Content of Laying Hens

The effect of dietary fish meal (FM) on production and egg yolk cholesterol of commercial Hyline White Leghorn hens (24-week old) was studied for four weeks. Eighty birds were given a corn-wheat-soyabean meal diet that contained either 0% (control diet, C) or 3% fish meal (DM basis). Hens were randomly divided into two experimental treatments with four replicates (10 hens per replicate). Egg weight, daily egg production (g/hen/day), daily feed consumption and feed conversion ratio were recorded. At the end of each week, 12 eggs from each group were randomly collected and egg yolk cholesterol, egg volume, shell thickness and Haugh unit (HU) were measured. There was no significant (p > 0.05) effect of feeding 3% FM on egg yolk cholesterol concentration (mg/100 g yolk or mg/yolk) compared with the control diet, but 3% FM, tended to decrease egg yolk cholesterol concentration (1930.93 vs 2021.48 mg/100 g yolk). Hens fed on 3% FM had higher (p < 0.05) egg production, egg weight, egg volume, shell thickness, HU and better feed conversion ratio. It was concluded that under the condition of the study, feeding 3% fish meal improved egg production traits but was not able to reduce cholesterol concentration of the egg yolk although tended to reduce cholesterol concentration.

Relationship between phytosterol levels and components of the metabolic syndrome in the PROCAM study

Components of the metabolic syndrome such as hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol and obesity have been shown to be associated with increased cholesterol synthesis and reduced cholesterol absorption. In the present study, we measured the lathosterol/cholesterol ratio as an index of cholesterol synthesis and the ratios of cholestanol, campesterol and sitosterol to cholesterol as indices of cholesterol absorption, as well as components of the metabolic syndrome, in 324 men and 168 women from the PROCAM study, an epidemiological study in which raised sitosterol was previously associated with increased coronary risk. Our aim was to determine if the indices of cholesterol synthesis and absorption show a graded relationship with severity of metabolic syndrome. No differences were seen between men and women with regard to the relationship of either the lathosterol/cholesterol or the sitosterol/cholesterol ratios and severity of metabolic syndrome. On multiple regression analysis in men and women together, body mass index showed a positive relationship with the lathosterol/cholesterol ratio (r=0.257, P<0.001) and a negative relationship with the sitosterol/cholesterol ratio (r=-0.221, P<0.001). HDL-cholesterol showed a negative relationship with the lathosterol/cholesterol ratio (r=-0.166, P=0.001). Triglycerides showed a negative relationship with the sitosterol/cholesterol ratio (r=0.141, P=0.005). Overall, these relationships were graded across quintiles of HDL cholesterol, body mass index and triglyceride and across an index of metabolic syndrome severity (number of components present). Only the cholestanol/cholesterol ratio showed a graded relationship with estimated overall coronary risk. The metabolic syndrome is associated with increased cholesterol synthesis and reduced cholesterol absorption in a relationship that is graded across severity of the individual components of the syndrome and across an index of the severity of the metabolic syndrome as a whole.

Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid

To address the effect of the n-3 fatty acid, docosahexaenoic acid (22:6), on proteins that play a role in cholesterol absorption, CaCo-2 cells were incubated with taurocholate micelles alone or micelles containing 22:6 or oleic acid (18:1). Compared with controls or 18:1, 22:6 did not interfere with the cellular uptake of micellar cholesterol. Apical cholesterol efflux was enhanced in cells incubated with 22:6. Cholesterol trafficking from the plasma membrane to the endoplasmic reticulum was decreased by 22:6. 22:6 decreased Niemann-Pick C1-Like 1 (NPC1L1) protein and mRNA levels without altering gene or protein expression of ACAT2, annexin-2, caveolin-1, or ABCG8. Peroxisome proliferator-activated receptor delta (PPARdelta) activation decreased NPC1L1 mRNA levels and cholesterol trafficking to the endoplasmic reticulum, suggesting that 22:6 may act through PPARdelta. Compared with hamsters fed a control diet or olive oil (enriched 18:1), NPC1L1 mRNA levels were decreased in duodenum and jejunum of hamsters ingesting fish oil (enriched 22:6). In an intestinal cell, independent of changes in ABCG8 expression, 22:6 increases the apical efflux of cholesterol. 22:6 interferes with cholesterol trafficking to the endoplasmic reticulum by the suppression of NPC1L1, perhaps through the activation of PPARdelta. Moreover, a diet enriched in n-3 fatty acids decreases the gene expression of NPC1L1 in duodenum and jejunum of hamster.

Effect of melatonin on cholesterol absorption in rats

This study evaluated the influence of melatonin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic and plasma total cholesterol, plasma very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, a decrease in high density lipoprotein (HDL) cholesterol and an elevation in triacylglyceride (TG) levels in plasma and in the liver. Melatonin suspension (10 mg/kg), specially prepared for this purpose, cholestyramine (230 mg/kg) and ezetimibe (145 microg/kg) were administered orally to the rats fed HCD for 30 days. Melatonin significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in total cholesterol, TG, VLDL- and LDL-cholesterol in the plasma and contents of cholesterol and TG in the liver. The level of HDL cholesterol was significantly increased after melatonin. These results suggested that inhibition of cholesterol absorption caused by melatonin could be a mechanism contributing to the positive changes in plasma cholesterol, lipoprotein profile and the lipid contents in the liver.

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice. Npc1l1(-/-)/apoE null-/- mice were generated and found to have a significant reduction in cholesterol absorption (-77%) compared with wild-type or apoE-/- mice. Npc1l1/apoE-/- mice were fed a chow or Western diet for 24 weeks, then lipoprotein, hepatic, and biliary cholesterol, and atherosclerosis development was compared with apoE-/-, Npc1l1-/-, wild-type, and ezetimibe-treated apoE-/- mice. Chylomicron remnant/VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet-fed Npc1l1/apoE-/- mice relative to apoE-/- mice. Male Npc1l1-/- and Npc1l1/apoE-/- mice were completely resistant to diet induced hypercholesterolemia, and both male and female mice were completely resistant to increases in hepatic and biliary cholesterol levels. Atherosclerosis was reduced 99% in aortic lesion surface area, 94% to 97% in innominate artery intimal lesion area, and >90% in aortic root lesion area in both male and female Npc1l1/apoE-/- mice relative to apoE-/- mice. Lack of Npc1l1, the molecular target of the cholesterol absorption inhibitor ezetimibe, in apoE-/- mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels, and causes a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non-cholesterol-fed conditions.

Phytosterols, Cholesterol Absorption and Healthy Diets

The purpose of this review is to outline the emerging role of dietary phytosterols in human health. Dietary saturated fat, cholesterol and fiber are currently emphasized in the reduction of low-density lipoprotein cholesterol levels. However, other dietary components such as phytosterols may have equivalent or even larger effects on circulating cholesterol and need further study with respect to the potential for coronary heart disease risk reduction. Phytosterol effects were not considered in classic fat-exchange clinical trials and may account for some of the differences attributed to the food fats studied. Phytosterols reduce cholesterol absorption while being poorly absorbed themselves and the effects can be studied in human subjects in single-meal tests using stable isotopic tracers. Because phytosterols are insoluble and biologically inactive when purified, careful attention needs to be given to ensuring that commercial supplement products are rendered bioavailable by dissolution in fat or by emulsification. Recent work shows that phytosterols in natural food matrices are also bioactive. The retention of phytosterols during food manufacturing and the use of foods with high phytosterol content may constitute an alternative to the use of supplements.

Dietary Plant Sterols and Cholesterol Metabolism

Plant sterols, naturally occurring in foods of plant origin, reduce cholesterol absorption. Experimental studies show plant sterols to be an important part of the serum-cholesterol lowering effect of certain diets and dietary components. Epidemiological data show that individuals with higher intakes of plant sterols from their habitual diets have lower serum-cholesterol levels. To date, the role of naturally occurring plant sterols for lowering serum cholesterol has probably been underestimated. The consumption of dietary plant sterols should be a part of dietary advice to patients with hypercholesterolemia and the general public for the prevention and management of coronary heart disease.