Meal-frequency effects on plasma hormone concentrations and cholesterol synthesis in humans.To examine meal-frequency effects on circulating hormone concentrations and cholesterol synthesis, male subjects consumed liquid diets given as either six evenly spaced (ES) or three diurnal (DI) meals over 3 d. Deuterium oxide was given on day 2 and blood sampled every 4 h over days 2 and 3 to measure plasma cholesterol, glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) concentrations and cholesterol synthesis. Cholesterol synthesis was determined from deuterium incorporation into plasma free cholesterol by using constrained and unconstrained curve-fit models. Plasma total cholesterol concentrations decreased in both ES and DI groups (P < 0.05). The ES group had lower insulin (P < 0.05) and GIP (P < 0.001) concentrations compared with the DI group. Cholesterol synthesis was reduced (P < 0.01) in the ES vs the DI group when determined by using constrained (0.050 +/- 0.002 vs 0.075 +/- 0.005 pools/d, respectively) and unconstrained (0.072 +/- 0.005 vs 0.119 +/- 0.011 pools/d, respectively) models. These data suggest meal frequency-dependent control of cholesterogenesis via hormonally mediated mechanisms.

Lipid profiles in untreated patients with rheumatoid arthritis.OBJECTIVE: To investigate lipid profiles in patients with untreated active rheumatoid arthritis (RA) and to assess the relationship of the inflammatory condition of RA with lipid profiles. METHODS: Forty-two patients with RA and 42 age and sex matched healthy controls were studied. Patients with RA had not been treated with corticosteroid or disease modifying antirheumatic drugs prior to the study. Total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apolipoprotein A1 (apo A1), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and C-reactive protein (CRP) were measured in both groups. RESULTS: The levels of apo A1 and HDL-cholesterol were significantly lower in patients than in controls (128.5 vs. 151.8 mg/dl, 41.2 vs. 54.9 mg/dl, respectively). The level of Lp(a) was significantly higher in patients than in controls (27.1 vs. 18.0 mg/dl). The ratios of apo B/apo A1, total cholesterol/HDL-cholesterol, and LDL-cholesterol/HDL-cholesterol were significantly higher in patients than in controls (0.82 vs. 0.67, 4.4 vs. 3.4, 2.8 vs. 1.9, respectively). CRP showed a significant correlation with apo A1 (r = -0.44, p<0.01) and HDL-cholesterol (r = -0.35, p<0.05). CONCLUSION: Our study suggests that patients with untreated active RA have altered lipoprotein and apolipoprotein patterns that may possibly expose them to higher risk of atherosclerosis. The inflammatory condition of RA may affect the metabolism of HDL-cholesterol and apo A1.

Coronary risk in growth hormone deficient hypopituitary adults: increased predicted risk is due largely to lipid profile abnormalities.BACKGROUND: Hypopituitarism in adults is associated with increased vascular mortality, which has been attributed to GH deficiency. OBJECTIVE: To compare the lipid profile and coronary risk predicted by the Framingham Heart Study equation in GH-deficient hypopituitary patients and healthy age and gender-matched controls. DESIGN: A cross-sectional observational study. METHODS: We studied 50 adult-onset growth hormone deficient hypopituitary patients (23F, 27M), on appropriate conventional hormone replacement and 45 controls (22F, 23M) matched for age, gender and smoking habit. The subjects (age range 30-75 years) were free from diabetes, hypertension, ischaemic heart disease (IHD) and peripheral vascular disease. All hypogonadal male patients were on testosterone replacement therapy. A similar proportion of female patients (8/23) and controls (7/22) were on HRT. Body mass index (BMI), waist-hip ratio (WHR) and blood pressure were recorded. After an overnight fast blood glucose, total-cholesterol, triglycerides, HDL-cholesterol, apolipoproteins A-I, B and Lp (a) were measured. Coronary risk was calculated for each individual from age, gender, systolic blood pressure, total and HDL cholesterol, smoking habit and presence of diabetes and left ventricular hypertrophy using the Framingham equation. RESULTS: BMI and WHR were significantly increased in GHD hypopituitary adults of both sexes, but to a greater extent in females. Triglycerides were elevated in both sexes. Total and LDL-cholesterol were increased in both sexes (significantly only in males), and HDL cholesterol and apo A-I were lower (significantly only in females). The reduction in HDL cholesterol was correlated negatively with adiposity (BMI), particularly when centrally distributed (WHR) in patients and controls. LDL cholesterol did not correlate to adiposity but higher levels were present in GH-deficient subjects. The total to HDL cholesterol ratio was significantly increased in patients of both genders (P = 0.002). There were no differences in the apolipoproteins B and Lp(a) between patients and controls. Absolute risk (mean +/- SEM) of a fatal or non-fatal coronary event during the next 5 years was significantly greater in GHD hypopituitary patients than control subjects (4.82 +/- 0.73% vs. 2.94 +/- 0.53, P = 0.04). Cardiovascular risk relative to the local population (RR) was significantly higher in GHD hypopituitary adults (RR = 1.43 CL 1.06-1.80, P = 0.011) but not in the control group (1.08 CL 0.59-1.6). When divided by gender, RR for male patients was not increased (1.14 CL 0.83-1.45, P = 0.096). However, female patients had significantly higher RR (1.7 CL 1.05-2.5, P = 0.048). The RR for male and female controls was not different from the local population. CONCLUSION: Changes in lipid levels help to explain the results from risk factor modelling which show increased coronary risk in growth hormone deficient hypopituitary patients, particularly females. The abnormal lipid profile is characterized in both genders by an increase in the total to HDL ratio [corrected], an important parameter in the Framingham equation. The lipid abnormalities conferring increased risk is related to growth hormone deficiency either directly (LDL) or indirectly through increased central obesity (HDL) [corrected]. Adverse calculated coronary risk might provide a new objective indication for consideration of GH replacement therapy in adults.

Control of human sperm intracellular pH by cholesterol and its relationship to the response of the acrosome to progesterone.When incubated in vitro, human sperm gradually become capable of acrosome-reacting in response to the agonist progesterone. Loss of unesterified cholesterol is required for sperm to become responsive to progesterone, but how cholesterol regulates acrosomal responsiveness is unknown. These experiments tested the hypothesis that loss of sperm cholesterol leads to a rise in the intracellular pH (pH(i)) that makes the sperm responsive to progesterone. pH(i) was measured using BCECF (2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein) in freshly ejaculated sperm (T0 sperm) and in sperm incubated in vitro overnight (T24 sperm). During incubation, pH(i) increased from 6.94 +/- 0.03 to 7.08 +/- 0.01 (mean +/- SEM, n = 4, p < 0.01). Incubating sperm 24 h in medium supplemented with 1 microM cholesterol to prevent loss of sperm cholesterol suppressed the rise of pH(i) (T24C sperm, pH(i) = 6.96 +/- 0.03, n = 4, p = 0.64 compared to T0 sperm). To test whether their lower pH(i) prevents T24C sperm from reacting, we treated T24C sperm with the alkalinizing agents trimethylamine chloride (TMA) or NH4Cl. These agents did cause T24C sperm to respond to progesterone in a dose-dependent fashion, but they also caused a similar increase in the number of reacting T24 sperm. These agents probably do not reverse the inhibiting effects of high cholesterol but rather make responsive a subpopulation of sperm that is present regardless of the cholesterol content. NH4Cl and TMA did not make T0 sperm responsive to progesterone. The acidifying agent sodium propionate did not diminish the response of T24 sperm to progesterone. In summary, pH(i) increases during incubation in vitro in a cholesterol-dependent fashion. Elevated pH(i) alone is probably not sufficient to make sperm acrosomally responsive.

Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse.HDL cholesterol levels in humans are inversely correlated with the risk of atherosclerosis. The class B scavenger receptor type I (SR-BI) is the first molecularly well-defined HDL receptor, and hepatic overexpression of SR-BI in normal mice has been shown to result in decreased plasma HDL cholesterol levels. To determine whether SR-BI overexpression is proatherogenic or is protective against atherosclerosis, LDL receptor-deficient mice were placed on a high-fat/high-cholesterol diet for 2 or 12 weeks to induce atherosclerotic lesions of different stages and then were injected with a recombinant adenovirus encoding murine SR-BI. Transient hepatic overexpression of SR-BI in mice with both early and advanced lesions significantly decreased atherosclerosis. SR-BI expression was associated with markedly decreased HDL cholesterol and either unchanged or only modestly reduced non-HDL cholesterol levels; in all experiments, the mean HDL cholesterol levels were significantly correlated with atherosclerotic lesion size. These data suggest that interventions that promote HDL cholesterol transport and lower plasma HDL cholesterol levels can suppress atherosclerosis, even when initiated after significant lesion development. Thus, stimulation of hepatic SR-BI activity may provide a novel target for therapeutic intervention in atherosclerotic cardiovascular disease.

Impact of obesity on lipid profiles in middle-aged women.OBJECTIVE: The goal of the study was to analyze the impact of overweight on lipid and apolipoprotein A-I and B (apoA-I, apoB) profiles in the women's blood serum. MATERIAL AND METHODS: Seventy-five women without any symptoms of Coronary Heart Disease were examined. Women were divided into two groups: those with normal weight and the body mass index (BMI) less than 25 (n=34, BMI 22.3+/-1.5; mean age 62+/-8.7 years) and overweight women (n=41, BMI 29.7+/-3.7; mean age 59+/-9.4). Weight and height were measured and blood serum concentrations of total cholesterol, high-density lipoprotein cholesterol, and triglycerides were determined after an overnight fasting. In the same serum samples the levels of apoA-I and B were measured using monoclonal antibodies against apo (Spinreact AA, Sant Esteve De Bas, Spain) by the immunoturbidimetry method. The serum samples were kept frozen at -40 degrees C until used. RESULTS: Total cholesterol and triglycerides levels were similar in the healthy and the overweight women groups (6.49+/-1.25 vs 6.52+/-1.18 mmol/l; p>0.05 and 1.21+/-0.71 vs 1.41+/-0.98 mmol/l; p>0.05, respectively). The concentrations of high-density lipoprotein cholesterol and apoA-I were significantly higher in the normal weight women compared to the overweight women (1.84+/-0.52 vs 1.40+/-0.29 mmol/l, p<0.001 and 1.40+/-0.26 vs 1.24+/-0.23 g/l, p<0.01, respectively). The level of apoB was significantly higher in the overweight female group compared to normal weight women (0.83+/-0.21 vs 0.74+/-0.18 g/l, p=0.049). The apoB/A-I ratio was significantly lower in the normal weight group than in the overweight group (0.055+/-0.15 vs 0.70+/-0.22; p<0.001). Moderate to strong correlations between apoA-I and high-density lipoprotein cholesterol concentrations were found in both groups (r=0.41, p<0.01 in the control female group and r=0.59, p<0.0001 in the overweight group, respectively). A similar level of correlation between apoB and total cholesterol was established in both groups (r=0.54, p<0.0005 and r=0.67, p<0.0001, respectively). CONCLUSION: Obesity in middle-aged women is associated with a significant decrease in serum high-density lipoprotein cholesterol and apoA-I levels, a significant increase in apoB and apoB/A-I ratio, even if serum total cholesterol and triglycerides concentrations are unaltered. Changes of the lipid profile in obese women are indicative of a higher risk of Coronary Heart Disease.

The hypercholesterolemic effect of cod protein is reduced in the presence of high dietary calcium.To determine the respective and interactive effects of dietary protein source and calcium level on serum, hepatic, and fecal lipid levels, 48 male New Zealand rabbits were fed purified diets varying in the source of dietary protein, namely casein, cod protein, or soy protein, at an adequate (7 mg Ca/g diet) or a high (14 mg Ca/g diet) concentration of calcium in a 3 x 2 factorial design for 28 days. Dietary proteins interacted with dietary calcium to modulate serum and low density lipoprotein (LDL) cholesterol. When combined with the adequate-calcium diet, code protein induced higher levels of serum and LDL cholesterol than casein and soy protein, induced lower serum and LDL cholesterol than when associated with an adequate concentration of calcium. These results indicate that the hypercholesterolemic effect of cod protein is reduced in the presence of high dietary calcium. Moreover, fecal lipid content was inversely correlated with serum total (p = 0.06) and LDL (p = 0.04) cholesterol in rabbits fed cod protein diets only. An increased formation of insoluble calcium phosphate in the intestine, which may result in lower fat intestinal absorption and serum cholesterol levels, may have been responsible for the decrease in serum and LDL cholesterol in rabbits fed cod protein with high dietary calcium.

Intake of dietary plant sterols is inversely related to serum cholesterol concentration in men and women in the EPIC Norfolk population: a cross-sectional study.OBJECTIVE: We examined the relation between intake of natural dietary plant sterols and serum lipid concentrations in a free-living population. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional population-based study of 22,256 men and women aged 39-79 y resident in Norfolk, UK, participating in the European Prospective Investigation into Cancer (EPIC-Norfolk). MAIN EXPOSURE AND OUTCOME MEASURES: Plant sterol intake from foods and concentrations of blood lipids. RESULTS: Mean concentrations of total cholesterol and low-density lipoprotein cholesterol, adjusted for age, body mass index and total energy intake, decreased with increasing plant sterol intake in men and women. Mean total serum cholesterol concentration for men in the highest fifth of plant sterol intake (mean intake 463 mg daily) was 0.25 mmol/l lower and for low-density lipoprotein cholesterol 0.14 mmol/l lower than those in the lowest fifth of plant sterol consumption (mean intake 178 mg daily); the corresponding figures in women were 0.15 and 0.13 mmol/l. After adjusting for saturated fat and fibre intakes, the results for total cholesterol and low-density lipoprotein cholesterol were similar, although the strength of the association was slightly reduced. CONCLUSIONS: In a free-living population, a high intake of plant sterols is inversely associated with lower concentrations of total and low-density lipoprotein serum cholesterol. The plant sterol content of foods may partly explain diet-related effects on serum cholesterol concentration.

Alterations in plasma lipids, lipoproteins and high density lipoprotein subfractions in peripheral arterial disease.The concentrations of the major lipoprotein classes and of high density lipoprotein (HDL) subfractions in 63 male patients with arteriosclerosis of the lower limbs (claudication) were determined and compared with values from 63 healthy controls. The patients with peripheral arterial disease (PAD) had reduced levels of total HDL-cholesterol and HDL2b of large particle size, increased levels of small HDL3c particles and a high ratio of total plasma-cholesterol to HDL-cholesterol (coronary risk factor). The PAD patients, however, had lower levels of low density lipoprotein (LDL)-cholesterol but higher concentrations of very low density lipoprotein (VLDL)-cholesterol and plasma triglyceride than healthy subjects. This study therefore suggests that in PAD, the protective effect of HDL may be more important than the atherogenic effect of LDL. It further suggests that while HDL-cholesterol HDL2b and the ratio of total plasma-cholesterol to HDL-cholesterol may provide valid indices for identifying individuals at risk of PAD, other factors, such as LDL and total cholesterol, may not provide such an appropriate risk indicator.

Ethanol-extracted soy protein isolate results in elevation of serum cholesterol in exogenously hypercholesterolemic rats.Soy protein preparations were reported to have hypocholesterolemic actions in experimental animals and humans, while the active components and the mechanism by which this occurs are not clarified yet. The objective of this study is to address these issues by using exogenously hypercholesterolemic rats which are susceptible to dietary cholesterol. Two groups of five rats (male, 12-wk-old) were fed on AIN 93G-based diet with soy protein isolate (SPI) or ethanol-extracted SPI (EE-SPI) for 2 wk. EE-SPI was prepared by ethanol extraction to remove isoflavones and other components. Concentrations of serum and liver total cholesterol were lower in rats fed SPI than in those fed EE-SPI. The abundances of mRNA for 7alpha-hydroxylase and low density lipoprotein receptor in the liver were lower in EE-SPI group than those in SPI group. These results suggest that the ethanol extract from SPI has a factor(s) to alleviate hypercholesterolemia by increasing the removal of cholesterol from serum through the receptor pathway and then from liver through enhancement of bile acid synthesis.