Diet, LDL oxidation, and coronary artery disease.
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Biomedical subjects
Publications and source records attributed to M B Katan.
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BACKGROUND: We determined the effect of oral ingestion of sucrose polyester, which was approved as a fat replacer in the United States, on gallbladder motility and on the release of cholecystokinin, the hormone that mediates gallbladder emptying. OBJECTIVE: Our objective was to measure effects of sucrose polyester on gallbladder emptying and cholecystokinin release. DESIGN: Eight healthy volunteers (3 men and 5 women) drank 60 mL sucrose polyester, digestible fat, or saline solution in a balanced crossover design on 3 separate days. RESULTS: Mean (+/-SEM) gallbladder emptying, when integrated over time, was low in response to both sucrose polyester (-150 +/- 214 mL x 120 min) and saline solution (-89 +/- 123 mL x 120 min). In contrast, there was marked emptying in response to digestible fat (1069 +/- 253 mL x 120 min). Sucrose polyester did not affect plasma cholecystokinin concentrations (-9.3 +/- 15.0 pmol x 120 min/L), whereas digestible fat resulted in a significant increase (89.5 +/- 44.8 pmol x 120 min/L, P = 0.014) compared with saline solution (-3.0 +/- 13.8 pmol x 120 min/L). CONCLUSIONS: Ingestion of sucrose polyester, in contrast with digestible fat, did not stimulate gallbladder emptying or release of cholecystokinin.
Quercetin is a strong antioxidant and a major dietary flavonoid. Epidemiological studies suggest that consumption of quercetin protects against cardiovascular disease, but its absorption in man is controversial. We fed nine subjects a single large dose of onions, which contain glucose conjugates of quercetin, apples, which contain both glucose and non-glucose quercetin glycosides, or pure quercetin-3-rutinoside, the major quercetin glycoside in tea. Plasma levels were then measured over 36 h. Bioavailability of quercetin from apples and of pure quercetin rutinoside was both 30% relative to onions. Peak levels were achieved less than 0.7 h after ingestion of onions, 2.5 h after apples and 9 h after the rutinoside. Half-lives of elimination were 28 h for onions and 23 h for apples. We conclude that conjugation with glucose enhances absorption from the small gut. Because of the long half-lives of elimination, repeated consumption of quercetin-containing foods will cause accumulation of quercetin in blood.
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Cafestol and kahweol-diterpenes present in unfiltered coffee-strongly raise serum VLDL and LDL cholesterol and slightly reduce HDL cholesterol in humans. The mechanism of action is unknown. We determined whether the coffee diterpenes may affect lipoprotein metabolism via effects on lipid transfer proteins and lecithin:cholesterol acyltransferase in a randomized, double-blind cross-over study with 10 healthy male volunteers. Either cafestol (61-64 mg/day) or a mixture of cafestol (60 mg/day) and kahweol (48-54 mg/day) was given for 28 days. Serum activity levels of cholesterylester transfer protein, phospholipid transfer protein and lecithin:cholesterol acyltransferase were measured using exogenous substrate assays. Relative to baseline values, cafestol raised the mean (+/- S.D.) activity of cholesterylester transfer protein by 18 +/- 12% and of phospholipid transfer protein by 21 +/- 14% (both P < 0.001). Relative to cafestol alone, kahweol had no significant additional effects Lecithin:cholesterol acyltransferase activity was reduced by 11 +/- 12% by cafestol plus kahweol (P = 0.02). It is concluded that the effects of coffee diterpenes on plasma lipoproteins may be connected with changes in serum activity levels of lipid transfer proteins.
The fatty acid composition of serum cholesteryl esters is used as a qualitative biomarker of fatty acid intake, but quantitative data are scarce. Between 1987 and 1992, the authors fed various fatty acids in four controlled trials to 232 healthy Dutch volunteers and measured the proportion of fatty acids in participants' cholesteryl esters. Each 10% of energy fed as linoleic acid (18:2) raised the proportion of linoleic acid in cholesteryl esters by 9.3 g per 100 g of fatty acids (standard deviation (SD) 3.1). For oleic acid (cis-18:1), this figure was 6.5 g/100 g (SD 1.7); for trans fatty acids (trans-18:1), it was 1.1 (SD 0.5); for stearic acid (18:0), 1.0 (SD 0.4); for palmitic acid (16:0), 1.7 (SD 0.5); for myristic acid (14:0), 2.1 (SD 0.7); and for a mixture of saturated fatty acids (12:0, 14:0, and 16:0), it was 2.2 g/100 g (SD 1.0). The coefficient of variation of the responses was fairly constant, indicating that changes in intake for each of these fatty acids can be monitored with similar precision. These data can be used to estimate the degree of compliance in experimental studies involving exchanges of single dietary fatty acids. Most fatty acids in cholesteryl esters may also be used in observational studies to estimate differences in intake. However, because of multiple simultaneous differences in fatty acid intake between free-living individuals and between populations, such data cannot provide information on absolute intake of fatty acids.
Quercetin, a dietary antioxidant flavonoid, has anticarcinogenic properties. We quantified the absorption of quercetin in ileostomists. Absorption was 52 +/- 5% for quercetin glucosides from onions, 17 +/- 15% for quercetin rutinoside, and 24 +/- 9% for quercetin aglycone. The plasma quercetin concentration in subjects with an intact colon, after ingestion of fried onions, apples and pure quercetin rutinoside, decreased slowly with elimination half-lives of about 25 h. Thus, repeated dietary intake of quercetin will lead to accumulation in plasma. The relative bioavailability of quercetin from apples and rutinoside was one-third of that from onions. Absorption kinetics and bioavailibility might be determined by the type of glycoside. Dietary quercetin could increase the antioxidant capacity of blood plasma.
Quercetin and related flavonoids are anticarcinogenic in rats, but little is known about human intakes. The intake of five major flavonols and flavones was calculated using 1-day dietary records of 17 volunteers from 14 countries, and using both 3-day records and a food frequency questionnaire of eight Dutch adults. Total consumption (+/- SD) was 27.6 +/- 19.5 mg/day in the international subjects, 34.1 +/- 31.2 mg/day in the Dutch adults according to 3-day records, and 41.9 +/- 23.7 mg/day according to questionnaires. Quercetin contributed 68-73%, and kaempferol 22-29%, the major sources being tea and onions. A brief food frequency questionnaire may be a suitable method for ranking individuals by flavonol intake.
Acetylsalicylic acid is effective in the prevention of cardiovascular disease. It was suggested that fruits and vegetables provide unknown amounts of acetylsalicylic acid. We could not find any acetylsalicylic acid in 30 foods using HPLC with fluorescence detection (detection limits: 0.02 mg/kg for fresh, and 0.2 mg/kg for dried products). We showed that urinary excretion of salicylates is a valid indicator for intake, and found a median salicylate excretion of 10 micromol (1.4 mg) in 24 h urine of 17 volunteers eating a variety of diets. Our data suggest that the content of (acetyl)salicylic acid of diets may be too low to affect disease risk.
Intake of trans fatty acids unfavorably affects blood lipoproteins. As margarines are a major source of trans, claims for the advantages of margarines over butter need to be scrutinized. Here we review dietary trials that directly compared the effects of butter and margarine on blood lipids. We identified 20 studies in which subjects had stable body weights, and margarine and butter were exchanged in the diet at constant energy and fat intake. We calculated the changes in average blood lipid levels between study diets (49 comparisons) as a function of the percentage of calories as margarine substituted for butter. Replacing 10% of calories from butter by hard high-trans stick margarines lowered total serum cholesterol by 0.19, LDL by 0.11, and HDL by 0.02 mmol/l, and did not affect the total/HDL cholesterol ratio. Soft low-trans tub margarines decreased total cholesterol by 0.25 and LDL by 0.20 mmol/l, did not affect HDL, and decreased the total/HDL cholesterol ratio by 0.20. Based on the total/HDL cholesterol ratio, replacement of 30 g of butter per day by soft tub margarines would theoretically predict a reduction in coronary heart disease risk of 10%, while replacement of butter by hard, high-trans margarines would have no effect. Replacing butter by low-trans soft margarines favorably affects the blood lipoprotein profile and may reduce the predicted risk of coronary heart disease, but high-trans hard margarines probably confer no benefit over butter.
Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4,000 different flavonoids have been described, and they are categorized into flavonols, flavones, catechins, flavanones, anthocyanidins and isoflavonoids. Flavonoids have a variety of biological effects in numerous mammalian cell systems, in vitro as well in vivo. Recently, much attention has been paid to their antioxidant properties and to their inhibitory role in various stages of tumour development in animal studies. Quercetin, the major representative of the flavonol subclass, is a strong antioxidant, and prevents oxidation of low density lipoproteins in vitro. Oxidized low density lipoproteins are atherogenic, and are considered to be a crucial intermediate in the formation of atherosclerotic plaques. This agrees with observations in epidemiological studies that the intake of flavonols and flavones was inversely associated with subsequent coronary heart disease. However, no effects of flavonols on cancer were found in these studies. The extent of absorption of flavonoids is an important unsolved problem in judging their many alleged health effects. Flavonoids present in foods were considered non-absorbable because they are bound to sugars as beta-glycosides. Only free flavonoids without a sugar molecule, the so-called aglycones, were thought to be able to pass through the gut wall. Hydrolysis only occurs in the colon by microorganisms, which at the same time degrade flavonoids. We performed a study to quantify absorption of various dietary forms of quercetin. To our surprise, the quercetin glycosides from onions were absorbed far better than the pure aglycone. Subsequent pharmacokinetic studies with dietary quercetin glycosides showed marked differences in absorption rate and bioavailability. Absorbed quercetin was eliminated only slowly from the blood. The metabolism of flavonoids has been studied frequently in various animals, but very few data in humans are available. Two major sites of flavonoid metabolism are the liver and the colonic flora. There is evidence for O-methylation, sulphation and glucuronidation of hydroxyl groups in the liver. Bacterial ring fission of flavonoids occurs in the colon. The subsequent degradation products, phenolic acids, can be absorbed and are found in urine of animals. Quantitative data on metabolism are scarce.
OBJECTIVE: Unfiltered coffee raises serum LDL cholesterol in humans, owing to the presence of the diterpenes cafestol and kahweol. Norwegians with a chronic high intake of unfiltered coffee also has elevated serum levels of lipoprotein(a), an LDL-like particle which is insensitive toward dietary interventions. We now experimentally studied the influence of coffee diterpenes on lipoprotein(a) levels. DESIGN: Four randomised controlled trials. SUBJECTS: Healthy, normolipidemic volunteers. INTERVENTIONS: Coffee, coffee oil, and pure diterpenes for 4-24 weeks. MAIN OUTCOME MEASURES: The circulating level of lipoprotein(a). RESULTS: In 22 subjects drinking five to six strong cups of cafetiere coffee per day, the median fall in lipoprotein(a) was 1.5 mg/dL after two months (P = 0.03), and 0.5 mg/dL after half a year (P > 0.05), relative to 24 filter coffee drinkers. Coffee oil doses equivalent to 10-20 cups of unfiltered coffee reduced lipoprotein(a) levels by up to 5.5 mg/dL (P < 0.05) in two separate trials (n = 12-16 per group). A purified mixture of cafestol and kahweol, as well as cafestol alone, were also effective in reducing Lp(a) levels (n = 10). Averaged over the four trials, each 10 mg/d of cafestol (plus kahweol)--the amount present in two to three cups of cafetiere coffee--decreased Lp(a) levels by 0.5 mg/dL or 4% from baseline values after four weeks (n = 63). CONCLUSIONS: Coffee diterpenes are among the few dietary exceptions shown to influence serum lipoprotein(a) levels. However, the Lp(a)-reducing potency of coffee diterpenes may subside in the long run, and their adverse side effects preclude their use as lipoprotein(a)-reducing agents.
Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.
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The coffee diterpene cafestol occurs in both robusta and arabica beans. It is present in unfiltered coffee brews and raises serum concentrations of cholesterol, triacylglycerols, and alanine aminotransferase in humans. The effects are linear with the cafestol dose. Unfiltered coffee also contains the related compound kahweol, which occurs only in the major coffee strain arabica. The activity of kahweol is unknown. In a randomized, double-blind crossover study, we gave 10 healthy male volunteers either pure cafestol (61-64 mg/d) or a mixture of cafestol (60 mg/d) and kahweol (48-54 mg/d) for 28 d. Relative to baseline values, cafestol raised mean (+/-SEM) total serum cholesterol concentrations by 0.79 +/- 0.14 mmol/L (31 +/- 5 mg/dL), low-density-lipoprotein (LDL) cholesterol by 0.57 +/- 0.13 mmol/L (22 +/- 5 mg/dL), fasting triacy-glycerols by 0.65 +/- 0.12 mmol/L (58 +/- 11 mg/dL), and alanine aminotransferase by 18 +/- 2 U/L (all P < 0.01). Relative to cafestol alone, the mixture of cafestol plus kahweol increased total cholesterol by another 0.23 +/- 0.16 mmol/L (9 +/- 6 mg/dL) (P = 0.08), LDL cholesterol by 0.23 +/- 0.16 mmol/L (9 +/- 6 mg/dL) (P = 0.09), triacylglycerols by 0.09 +/- 0.10 mmol/L (8 +/- 9 mg/dL) (P = 0.20), and alanine aminotransferase by 35 +/- 11 U/L (P = 0.004). Thus, the effect of cafestol on serum lipid concentrations was much larger than the additional effect of kahweol, and the hyperlipidemic potential of unfiltered coffee mainly depends on its cafestol content. Both cafestol and kahweol raised alanine aminotransferase concentrations, and their hyperlipidemic effect thus seems not to be coupled with their effect on liver cells.
Replacement of dietary fat by sucrose polyester reduces fat intake. However, little is known about the effects of sucrose polyester on gastrointestinal function. To investigate the effect on gastric acid secretion and on release of cholecystokinin into plasma, we perfused eight healthy male volunteers intraduodenally with sucrose polyester, digestible fat, or saline on separate days in random order. Intraduodenal perfusion of sucrose polyester did not suppress gastrin-stimulated gastric acid secretion (-1.8 +/- 6.8%) whereas digestible fat suppressed gastric acid secretion by 64 +/- 9% (P = 0.001) compared with saline. Sucrose polyester did not affect plasma cholecystokinin concentrations (-12.8 +/- 9.3 pmol.30 min/L) whereas perfusion with digestible fat resulted in a significant increase (31.7 +/- 9.3 pmol.30 min/L, P = 0.017) compared with saline. We conclude that sucrose polyester, in contrast with digestible fat, does not inhibit gastrin-stimulated gastric acid secretion or stimulate release of cholecystokinin.
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Protein-energy malnutrition is thought to be widespread in hospitalized patients. However, the specificity of indexes used to assess malnutrition is uncertain. We therefore assessed the rate of false-positive diagnoses of malnutrition when biochemical-anthropometric indexes were applied to healthy subjects. Nutritional status was assessed in 175 healthy blood donors (aged 44.2 +/- 13.4 y) and in 34 highly fit elderly volunteers (aged 74.7 +/- 3.6 y) participating in the Nijmegen Four Days Walking March. We investigated both the Nutritional Risk Index [(1.489 x albumin) + (41.7 x present/usual weight)] and the Maastricht Index [20.68-(0.24 x albumin, g/L)-(19.21 x serum transthyretin, g/L)-(1.86 x lymphocytes, 10(6)/L)-(0.04 x ideal weight)]. We found previously that 52-64% of nonsurgical hospitalized patients were malnourished according to these indexes. In the present study, 1.9% of the 209 volunteers had apparent malnutrition according to the Nutritional Risk Index and 3.8% according to the Maastricht Index. The prevalence of apparent malnutrition in the elderly volunteers was 5.9% and 20.6%, respectively. The rate of false-positive diagnoses was acceptably low in those aged < 70 y with both the Nutritional Risk Index and the Maastricht Index; therefore, the use of these indexes will not cause a clinically significant increase in the prevalence of malnutrition because patients who are not malnourished are included. The high percentage of spurious malnutrition in the elderly limits the use of the Maastricht Index to subjects aged < 70 y.