BACKGROUND: Humans and animals show a certain consistency in the response of their serum lipids to fat-modified diets. This may indicate a genetic basis underlying this response. Coffee oil might be used as a model substance to investigate which genes determine differences in the serum lipid response. Before carrying out such studies our objective was to investigate to what extent the effect of coffee oil on serum lipid concentrations is reproducible within subjects. METHODS: The serum lipid response of 32 healthy volunteers was measured twice in separate five-week periods in which coffee oil was administered (69 mg cafestol/day). RESULTS: Total cholesterol levels increased by 24% in period 1 (range: 0;52%) and 18% in period 2 (1;48%), LDL cholesterol by 29 %(-9;71%) and 20%(-12;57%), triglycerides by 66%(16;175%) and 58%(-13;202%), and HDL cholesterol did not change significantly: The range of the HDL response was -19;25% in period 1 and -20;33% in period 2.The correlation between the two responses was 0.20 (95% CI -0.16, 0.51) for total cholesterol, 0.16 (95% CI -0.20, 0.48) for LDL, 0.67 (95% CI 0.42, 0.83) for HDL, and 0.77 (95% CI 0.56, 0.88) for triglycerides. CONCLUSIONS: The responses of total and LDL cholesterol to coffee oil were poorly reproducible within subjects. The responses of HDL and triglycerides, however, appeared to be highly reproducible. Therefore, investigating the genetic sources of the variation in the serum-lipid response to coffee oil is more promising for HDL and triglycerides.

The St. Thomas mixed hyperlipidaemic (SMHL) rabbit exhibits an inherited hyperlipidaemia similar to that seen in familial combined hyperlipidaemia (FCHL). In this study, we investigated whether the SMHL rabbit is insulin resistant, a condition often associated with FCHL. Six young and six mature combined hyperlipidaemic SMHL rabbits, age/sex matched New Zealand White (NZW) control rabbits and six young hypercholesterolaemic Watanabe heritable hyperlipidaemic (WHHL) control rabbits were fed a 0.08%(w/w) cholesterol-enriched diet for at least 1 month prior to the start of the experiment. We performed an oral glucose tolerance test after an overnight fast by dosing the rabbits with a solution of 1 g of glucose per kg body weight. Blood was withdrawn just before and 15, 30, 45, 60 and 120 min after administration of the oral glucose dose. Plasma glucose levels were similar in SMHL, WHHL and NZW rabbits throughout the oral glucose tolerance test. Fasting glucose levels were slightly increased in WHHL rabbits but not in young and adult SMHL rabbits as compared to NZW rabbits. The area under the curve (AUC) for the insulin response was significantly increased for both young (P<0.05) and mature (P<0.05) SMHL rabbits, and in WHHL rabbits, compared with NZW rabbits. The AUC for the ratio of glucose:insulin response to the glucose dose was decreased in young and mature SMHL rabbits (P<0.05 and P<0.01, respectively) and in young WHHL rabbits (P<0.05), compared with NZW rabbits. Only WHHL rabbits showed an increased AUC for the non-esterified fatty acid response compared to NZW rabbits. Log-transformed plasma triglycerides values were significantly correlated with the log-transformed AUC for the insulin response in young SMHL rabbits (r=0.81; P<0.05) and with the AUC for the insulin response in mature SMHL rabbits (r=0.84; P<0.05). WHHL rabbits showed no significant correlation. In conclusion, SMHL rabbits are insulin resistant, the severity of which appears to increase with age. Therefore, the SMHL rabbit offers a valuable animal model in which to study the relation between hypertriglyceridaemia and insulin resistance.

Apolipoprotein B (apoB) metabolism was investigated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6. 95 mmol/l. Kinetics of VLDL(1)(S(f) 60-400), VLDL(2)(S(f) 20-60), IDL (S(f) 12-20), and LDL (S(f) 0;-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL(1) apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL(2) apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride (r =-0.54, P = 0.009). Percent of direct apoB production into the IDL/LDL density range (r = 0.50, P < 0.02) was positively related to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined principally by VLDL(1) and VLDL(2) apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR (r =-0.71, P < 0.0001). LDL apoB concentration correlated with VLDL(2) apoB production (r = 0.48, P = 0.018) and the LDL FCR (r =-0.77, P < 0. 001) but not with VLDL(1), IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL(1) and VLDL(2) apoB FTRs, higher VLDL(2) apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This latter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles.

Phenolic compounds in red wine may protect low-density lipoproteins (LDL) against oxidative modification, thereby reducing the risk of cardiovascular morbidity. However, in vivo data are scarce. We gave 13 healthy volunteers 550 mL red wine and another 11 volunteers white wine for 4 wk in a randomized double-blind trial. Interference by alcoholic components of wine was eliminated by reducing the alcohol content to 3.5% Red wine did not affect the susceptibility of LDL to Cu2+-mediated oxidative modification [lag time before and after red wine drinking (chi +/- SD) 61.8 +/- 7.7 and 62.7 +/- 11.8 min, respectively; lag time before and after white wine drinking: 64.5 +/- 10.4 and 63.3 +/- 10.8 min, respectively]. Concentrations of the antioxidants urate, vitamin C, and glutathione in plasma and of vitamin E and ubiquinol-10 in LDL were also unchanged after either red or white wine consumption. The results of this study do not show a beneficial effect of red wine consumption on LDL oxidation.

VLDL1, VLDL2, IDL, and LDL and its subfractions (LDL-I, LDL-II, and LDL-III) were quantified in 304 normolipemic subjects together with postheparin plasma lipase activities, waist/hip ratio, fasting insulin, and glucose. Concentrations of VLDL1 and VLDL2 rose as plasma triglycerides (TGs) increased across the normal range, but the association of plasma TGs with VLDL1 showed a steeper slope than that of VLDL2 (P <.001). Plasma TG level was the most important determination of LDL subfraction distribution. The least dense species, LDL-I, decreased as the level of this plasma lipid rose in the population. LDL-II in both men and women exhibited a positive association with plasma TG level in the range 0.5 to 1.3 mmol/L, increasing from about 100 to 200 mg/dL. In contrast, within this TG range the LDL-III concentration was low (approximately equal to 30 mg/dL) and changed little. As plasma TGs rose from 1.3 to 3.0 mmol/L there was a significant fall in LDL-II concentration in men (r =.45, P <.001) but not in women (r =.1, NS). Conversely, above the TG threshold of 1.3 mmol/L there was a steeper rise in LDL-III concentrations in men than in women (P <.001); 42% of the men had and LDL-III in the range associated with high risk of heart disease (> 100 mg lipoprotein/dL plasma) compared with only 17% of the women. Other influences on the LDL subfraction profile were the activities of lipases and parameters indicative of the presence of insulin resistance. Men on average had twice the hepatic lipase activity of women. This enzyme was not strongly associated with variation in the LDL subfraction profile in men, but in women it was correlated with LDL-III (r = 39, P =.001) and remained a significant predictor in multivariate analysis. Increased waist/hip ratio, fasting insulin, and glucose were correlated negatively with LDL-I and positively with LDL-III, primarily, at least in the case of LDL-III, through raising plasma TGs. On the basis of these cross-sectional observations we postulate the following model for the generation of LDL-III. Subjects develop elevated levels of large TG-rich VLDL1 for a number of reasons, including failure of insulin action. The increase in the concentration of VLDL1 expands the plasma TG pool, and this, via the action of cholesteryl ester transfer protein (which facilitates neutral lipid exchange between lipoprotein particles), promotes the net transfer of TGs into LDL-II, the major LDL species.(ABSTRACT TRUNCATED AT 400 WORDS)

Previous studies have indicated that consumption of boiled coffee raises total and low density lipoprotein (LDL) cholesterol, whereas drip-filtered coffee does not. We have tested the effect on serum lipids of consumed coffee that was first boiled and then filtered through commercial paper coffee filters. Sixty-four healthy volunteers consumed six cups per day of this boiled and filtered coffee for 17 days. Then, they were randomly divided into three groups, which, for the next 79 days, received either unfiltered boiled coffee (lipid content, 1.0 g/l), boiled and filtered coffee (0.02 g lipid/l), or no coffee. Serum total cholesterol levels rose by 0.42 mmol/l (16 mg/dl; 95% confidence interval [CI], 0.14-0.71), LDL cholesterol levels by 0.41 mmol/l (16 mg/dl; 95% CI, 0.16-0.66), and apolipoprotein B levels by 8.6 mg/dl (95% CI, 3.8-13.4) in those who consumed boiled coffee relative to those who consumed boiled and filtered coffee. Responses of triglycerides, high density lipoprotein cholesterol, and apolipoprotein A-I did not differ significantly among these groups. No significant effects on serum lipid levels were found in the boiled and filtered coffee-consuming group compared with those who drank no coffee. In subjects who drank boiled coffee, serum campesterol level, an indicator of cholesterol absorption, remained constant. The serum lathosterol level, an indicator of cholesterol synthesis, increased by 11%(p less than 0.05), but the lathosterol to cholesterol ratio did not change. We propose that paper filters of the type used for drip-filtered coffee retain the lipid present in boiled coffee and in that way remove the hypercholesterolemic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effect of two diets, one rich in polyunsaturated and the other in saturated fatty acids, on the postprandial processing of exogenous and endogenous triglyceride-rich lipoproteins (chylomicrons, very-low-density lipoproteins, and their remnants). For this purpose, 12 normolipidaemic young volunteers were fed, in a cross-over design of 9 days on each diet, either a diet rich in saturated fat (21% of their daily energy intake from saturated fat, 12% from monounsaturated fat, and 3% from polyunsaturated fat) or a diet rich in polyunsaturated fat (10% saturated fat, 9% monounsaturated fat, and 18% polyunsaturated fat)(P/S ratios 0.14 and 1.8, respectively). On the last day of each dietary period blood samples were drawn six times over a 24-h period for determination, by densitometric scanning of SDS gels, of the diurnal pattern of apoprotein B-48 and B-100 in the d less than 1.019 g ml-1 fractions, as estimates for the processing of chylomicrons and very-low-density lipoproteins. In addition to the usual decrease in the fasting and diurnal concentrations of total serum cholesterol and of cholesterol in the low-density lipoprotein fractions (between 15 and 21%), the diet rich in polyunsaturated fat resulted in 43% lower daily concentrations of chylomicrons and their remnants. This was due to differences in the clearance rate of chylomicrons and their remnants, rather than to differences in the absorption rate of exogenous fat. In addition, the concentrations of very low density lipoproteins and their remnants during the day were 20% lower on the diet rich in polyunsaturated fat.(ABSTRACT TRUNCATED AT 250 WORDS)

Very low density lipoprotein (VLDL) 1 and 2 were fractionated by heparin affinity chromatography into a bound and an unbound fraction and the different subfractions were quantified in 17 normolipidaemic (NL), 13 hypercholesterolaemic (HC), 10 hypertriglyceridaemic (HTG) and 11 combined hyperlipidaemic subjects (CHL). Unbound VLDL1 and VLDL2 were, respectively, 1.9- and 2.2-fold richer in triglycerides than bound VLDL1 and VLDL2. In HTG and CHL the concentration of all the VLDL subfractions was increased and plasma triglyceride level was correlated to unbound VLDL1 and to bound VLDL1 (respectively, r=0.86 (p<0.001) and r=0.77 (p<0.01) in HTG and r=0.73 (p<0.001) and r=0.62 (p<0.05) in CHL). In HC unbound VLDL2 and bound VLDL2 concentration were increased compared to NL and in CHL, the concentration of bound VLDL2 was particularly increased (3.2-fold compared to NL (p<0.001)). In both HC and CHL bound VLDL2 concentration was correlated to low density lipoprotein cholesterol (LDL-C) concentration (respectively, r=0.67 (p<0.01) and r=0.62 (p<0.05)). In hypertriglyceridaemic states the intravascular accumulation of both unbound and bound VLDL1 appears as the determinant of plasma triglyceride concentration, whereas in moderately hypercholesterolaemic states the concentration of bound VLDL2 is strikingly correlated to LDL-C concentration, suggesting that these two species are linked metabolically, e.g. bound VLDL2 contain the precursor pool of LDL.

The role of the apo E polymorphism in the removal of remnants of very low density lipoproteins and chylomicrons was studied after a carbohydrate-rich diet in 10 healthy normolipidemic volunteers with different apo E phenotypes during 7 days. The cholesterol concentration in the heparin-sepharose bound part of the VLDL + IDL fraction (d < 1.019 g/ml) was taken as an estimate of the remnant concentration. Before and after carbohydrate-rich diet retinyl palmitate, mixed with cream, was consumed by each subject the evening before the fasting venepuncture to quantify the removal of chylomicron remnants. After the diet there was a comparable mean rise in the three groups in serum and in very low density lipoprotein triglycerides of about 30% and 50%, respectively. The concentration of remnants of very low density lipoproteins increased slightly in all subjects. The concentration of retinyl palmitate in the d < 1.019 g/ml fraction was 20% lower than before this diet in the E-2 homozygous subjects. In the other two groups, however, 25 to 80% higher retinyl palmitate levels were found. It is concluded, that after a carbohydrate-rich diet there is only a slight increase of very low density lipoprotein remnants, independent of the apo E polymorphism. The removal of chylomicron remnants, however, seems to be facilitated in E-2 homozygous subjects, in contrast to a slower removal in the groups with other apo E phenotypes.

Cafestol and kahweol, coffee-specific furan diterpenes, are believed to cause various physiological effects in human subjects, including an increase in cholesterol and plasma triacylglycerol levels as well as cancer chemopreventive effects. Despite the increasing interest in these compounds raised by the diverse range of biological activities, their reaction behavior and degradation pathways under physiologically relevant conditions remain uncharted. Herein, we report a detailed investigation of the structural modifications suffered by cafestol and kahweol in the presence of acidic nitrite under conditions mimicking those occurring in the stomach during digestion as well as by action of other oxidants. Prior to the chemical study, an isolation procedure for kahweol from green coffee beans was developed based on Soxhlet extraction followed by preparative HPLC. Preliminary experiments showed that kahweol is much more reactive than cafestol toward nitrite at pH 3, as evidenced by inhibition experiments with the 2,3-diaminonaphthalene assay as well as by product analysis in coffee extracts. When exposed to equimolar nitrite in phosphate buffer, pH 3, kahweol gave as a main product the ring-opened dicarbonyl derivative 1. Under more forcing conditions, cafestol reacted as well to give a main nitrogenous product identified as the 1-hydroxy-2-pyrrolinone 2. It is concluded that the conjugated double bond in kahweol is a critical structural element, increasing the susceptibility of the furan ring to protonation rather than nitrosation and favoring ring-opening routes driven by the irreversible oxidation steps. These results offer a useful background to assess the effects of coffee-specific lipids in association with abnormally high nitrite levels from the diet.

AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.

Very low-density lipoprotein triacylglycerol (VLDL-TG) turnover rate was evaluated in the morning, 12 hours after a single bout of brisk walking (90 minutes at approximately 60% of Vo(2)max; EXE), compared to a resting control period (CON) in 10 recreationally active men. VLDL-TG fractional catabolic rate was calculated from the decay in isotopic enrichment after a bolus injection of [(2)H(5)]glycerol. Plasma VLDL-TG concentration was 24% lower in the morning after the EXE trial compared to control (0.47 +/- 0.04 and 0.36 +/- 0.04 mmol L(-1), for CON and EXE, respectively; P <.01). Serum insulin (7.4 +/- 0.7 and 5.6 +/- 0.4 mIU L(-1), CON and EXE, respectively; P <.05) and plasma glucose (5.6 +/- 0.1 and 5.4 +/- 0.1 mmol/L, CON and EXE, respectively; P <.05) concentrations were also significantly lower in the EXE trial. Insulin sensitivity (homeostasis model assessment [HOMA] index) was improved by 27% in EXE compared with the CON trial (P <.05).VLDL-apolipoprotein B-100 and plasma fatty acid concentrations were similar in the two trials. Hepatic VLDL-TG secretion rates were not significantly affected by exercise (13.1 +/- 1.2 and 13.2 +/- 1.6 mumol(.)min(-1) for the CON and EXE trials, respectively), whereas VLDL-TG clearance rate increased by 36%(28.1 +/- 1.3 and 38.1 +/- 3.5 mL(.)min(-1) for the CON and EXE trials, respectively; P <.05). It is concluded that the decrease in fasting plasma VLDL-TG concentration observed 12 hours after brisk walking is related mainly to increased VLDL-TG clearance from plasma.

OBJECTIVE: To determine the amounts of the serum-cholesterol raising diterpenes cafestol and kahweol in coffee made with coffee pads and the Senseo coffee machine as opposed to filtered and unfiltered coffee. DESIGN: Observational. METHOD: In five cities in the Netherlands coffee was purchased in three major supermarkets resulting in a total of 30 samples of coffee pads. The levels of cafestol and kahweol were determined by gas chromatography. As controls, the diterpene levels in filtered and unfiltered coffee were also measured. RESULTS: Coffee prepared using coffee pads contained on average 0.76 mg/l cafestol (95% CI: 0.69-0.82) and 0.85 mg/l kahweol (95% CI: 0.77-0.94). Filtered coffee contained 0.76 mg/l cafestol (95% CI: 0.63-0.88) and 0.81 mg/l kahweol (95% CI: 0.63-0.99). Unfiltered coffee contained 72.5 mg/l cafestol (95% CI: 48.5-96.4) and 71.5 mg/l kahweol (95% CI: 45.0-98.1). CONCLUSION: Coffee prepared using coffee pads and the Senseo coffee machine contained minute levels of diterpenes comparable to those of filtered coffee. Its effect on serum-cholesterol levels is therefore likely to be negligible.

BACKGROUND: Lipoprotein lipase (LPL) deficiency has been suggested as a cause of low HDL-cholesterol (HDL-C) plasma levels, by a mechanism that involves an enhanced catabolism of HDL apolipoprotein (apo) AI. To verify the role of 2 different LPL gene mutations on HDL metabolism, we studied the in vivo turnover of the apo AI and apo AII in heterozygous carriers of LPL deficiency. METHODS: Apo AI and AII kinetics were studied by a 10-h primed constant infusion of 5,5,5-2H3-leucine approach in 2 carriers, 1 man (patient 1) and 1 woman (patient 2), and 5 control subjects. The rates of HDL apolipoproteins production (PR) and catabolism (FCR) were estimated using a one-compartment model-based analysis. RESULTS: Both carriers had low HDL-C plasma levels and only patient 1 was hypertriglyceridemic. VLDL apo B was 4-times slower in patient 1 as compared to patient 2. The FCRs of apo AI in both carriers was within the range of the controls (0.200, 0.221 and 0.211+/-0.051 day(-1), respectively). Apo AII FCR in patient 1 was about 20% lower than the mean of the control group whereas being normal in patient 2. Apo AI PR in patient 1 (9.20 mg kg(-1) day(-1)) was below the lowest value in controls (range, 10.52-13.24 mg kg(-1) day(-1)) whereas in patient 2 it was normal. Apo AII PR in both patients was similar to controls. CONCLUSION: The heterozygous carriers of 2 different mutations in the LPL gene had different VLDL apo B FCR, and from normal to slightly low HDL apolipoprotein FCR and PR. These results disagree with the putative enhanced apo AI FCR in LPL deficient patients and suggest the need to reconsider the effects of LPL activity on HDL metabolism.

BACKGROUND: Fatty infiltration of the liver is associated with an increased morbidity and mortality in children with severe protein-energy malnutrition (PEM), but its pathogenesis remains unclear. Although impaired synthesis of VLDL apolipoprotein B-100 (VLDL-apo B-100) is generally accepted as the pathogenetic mechanism, the rate of it synthesis has not been measured in children with PEM. OBJECTIVE: The objective of the study was to ascertain the relation between the degree of hepatic steatosis and the rate of VLDL-apo B-100 synthesis in children with PEM. DESIGN: The fractional and absolute rates of VLDL-apo B-100 synthesis were measured with a prime-constant intravenous infusion of [2H3]leucine in 13 severely malnourished children (8 boys and 5 girls) aged 7-18 mo. Hepatic fat content was estimated by computerized tomography scanning by using the ratio of liver to spleen (L:S) attenuation. The ratio is inversely related to hepatic fat content such that the lower the L:S, the greater the amount of fat in the liver. RESULTS: There were significant inverse relations between L:S attenuation and VLDL-apo B-100 concentration (P < 0.02), the absolute rate of VLDL-apo B-100 synthesis (P < 0.02), and plasma triacylglycerol (P < 0.02) and serum cholesterol (P < 0.05) concentrations. CONCLUSIONS: These results suggest that children with PEM synthesize VLDL-apo B-100 at a faster rate as the degree of hepatic fat infiltration increases. Thus, fatty infiltration of the liver in PEM is not due to a reduction in the synthesis of VLDL-apo B-100.

Unfiltered coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol in humans. Cafestol decreases the expression and activity of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7alpha-hydroxylase in humans. Because liver biopsies were not feasible, we measured plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol 7alpha-hydroxylase in the liver. Plasma 7alpha-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing cafestol (69 mg/d) for 5 wk. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one increased by 47 +/- 13%(mean +/- SEM, n = 38, P = 0.001) in the first period and by 23 +/- 10%(n = 31, P = 0.03) in the second treatment period. Serum cholesterol was raised by 23 +/- 2%(P < 0.001) in the first period and by 18 +/- 2%(P < 0.001) in the second period. We corrected individual 7alpha-hydroxy-4-cholesten-3-one levels for serum cholesterol levels, because coffee oil increases serum cholesterol and 7alpha-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the increase in 7alpha-hydroxy-4-cholesten-3-one was 24 +/- 11%(P = 0.04) in the first period and there was no effect in period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7alpha-hydroxy-4-cholesten-3-one in humans in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in humans.

The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL(1) and VLDL(2) after a bolus injection of [(2)H(3)]leucine and [(2)H(5)]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL(1) and VLDL(2) apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL(1) TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver.

BACKGROUND: Apolipoprotein A5 plays an important role in modulating triacylglycerol metabolism in experimental animal models. OBJECTIVE: The objective was to determine associations of the common apolipoprotein A5 gene (APOA5)-1131T-->C polymorphism with postprandial lipemic response and other cardiovascular disease risk factors in humans. DESIGN: Healthy, nonobese subjects [n = 158; mean (+/-SEM) age: 33.8 +/- 1.2 y; body mass index (in kg/m(2)): 23.3 +/- 0.3] were subdivided into 3 genotype groups: TT (n = 85), TC (n = 56), and CC (n = 17). We measured fasting and postprandial lipid concentrations, lipid peroxidation, C-reactive protein concentrations, and DNA damage. RESULTS: Fasting triacylglycerol concentrations in carriers of the C allele were higher (P < 0.05) than in carriers of the TT genotype. No other significant genotype-related differences were observed for any of the other baseline measures. After consumption of a mixed meal, carriers of the C allele had significantly greater increases in total chylomicron and VLDL triacylglycerol than did subjects with the TT genotype. Moreover, carriers of the C allele had higher dense LDL, serum C-reactive protein, and urinary 8-epi-prostaglandin F(2alpha) concentrations and more lymphocyte DNA damage. Conversely, we did not find significant genotype-related differences in postprandial glucose, insulin, or free fatty acid measures. CONCLUSIONS: Our data confirm the genetic modulation of serum fasting triacylglycerol concentrations by the APOA5 gene polymorphism and extend this observation to postprandial triacylglycerol concentrations and to markers of oxidation and inflammation. The presence of the C allele in the APOA5 promoter region at position 1131 could be a significant factor contributing to higher cardiovascular disease risk in Koreans independently of common environmental factors.