Changes In Plasma Cholesterol Research Articles

Changes in plasma lipids and lipoproteins following 10-days of prolonged walking: influence of age and relationship to physical activity level

The aim of the present study was to examine (1) the influence of 10 days of prolonged walking on plasma total-cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) concentrations, (2) the effect of age on any changes in plasma cholesterol and lipoprotein concentration, and (3) whether any changes in cholesterol and lipoprotein concentrations are correlated to the participants' physical activity level (PAL). Seventeen male participants were divided into two groups according to their age. The nine participants in group 1 constituted the younger group (age 24 ± 3 (SD) years), whereas eight older participants were in group 2 (age 56 ± 3 years). Both groups completed 10 consecutive days of high-intensity hill walking. Mean (range) daily distances and ascent were 21 km (10–35 km) and 1,160 m (800–2,540 m), respectively. Identical distances and ascents were covered by each group. For each participant, PAL was calculated from energy expenditure, assessed by the doubly-labeled water technique, divided by the individual's basal metabolic rate. Venous blood was sampled immediately prior to, and following, the 10 consecutive days of walking. Following these 10 days, the older group showed a greater decrease in both TC (−25 ± 11% vs. −10 ± 11%; P < 0.05) and LDL-C (−26 ± 12% vs. −4 ± 13%; P < 0.05) when compared with the young. Likewise, the older group showed a greater increase in HDL-C (38 ± 15%; P < 0.05), after the 10 days, whereas no significant change was evident in the younger group. In the older participants, there were strong positive relationships between PAL and the decreases in TC (r = 0.79, P < 0.05) and LDL-C (r = 0.74, P < 0.05). Conversely, in the younger group there were strong negative relationships between PAL and the decreases in TC (r = −0.74, P < 0.05) and LDL-C (r = −0.86, P < 0.01). These correlations persisted when changes in lipid concentrations were corrected for changes in plasma volume. These data suggest an ‘age-dependant’ threshold for PAL, rather than a specific exercise intensity or duration, may be critical for inducing favourable changes in HDL-C, LDL-C and TC.

Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the accumulation of plasma LDL-sized lipoproteins, VLDLR or LRP deficiency alone only minimally affects plasma lipoproteins. To investigate the combined effect of the absence of these receptors on TG-rich lipoprotein levels, we have generated unique VLDLR, LDLR, and LRP triple-deficient mice. Compared with wild-type mice, these mice markedly accumulated plasma lipids and lipases. These mice did not show aggravated hyperlipidemia compared with LDLR and LRP double-deficient mice, but plasma TG was increased after high-fat diet feeding. In addition, these mice showed a severely decreased postprandial TG clearance typical of VLDLR-deficient (VLDLR-/-) mice. Collectively, although VLDLR deficiency in LRP- and LDLR-/- mice does not aggravate hyperlipidemia, these triple-deficient mice represent a unique model of markedly delayed TG clearance on a hyperlipidemic background.

Beneficial effects of weight loss on plasma apolipoproteins in postmenopausal women

A total of 39 postmenopausal women 40–70 years of age and undergoing hormone replacement therapy participated in a 6-month weight reduction program, which consisted of a low calorie diet (5040 KJ/day) and phentermine hydrochloride therapy. Subjects had an average body mass index of 35.95±5.32 kg/m 2 and 42.20±11.0 kg of total fat. Body mass index, plasma lipids, total and trunk fat, and plasma apoproteins were measured at baseline and after 3 and 6 months of the weight reduction program. Subjects experienced an overall 10% weight loss during the treatment period ( P<0.001). Plasma LDL cholesterol and triglycerides were reduced by 18% and 15% ( P<0.01) respectively, whereas HDL cholesterol was increased by 9% ( P<0.01) over the 6-month period. Plasma apoproteins were significantly affected by weight loss. Plasma apolipoprotein (apo) B concentrations were reduced 6.5% ( P<0.01), and apo C-III and apo E were reduced by 9% over 6 months ( P<0.01). The observed decreases in plasma apo B were significantly correlated with the observed changes in plasma cholesterol ( r=0.356, P<0.01) over 3 months. In addition, changes in plasma triglycerides were correlated with changes in both apo C-III ( r=0.436) and apo E ( r=0.354) over 6 months. These results suggest that weight loss may have multifactorial effects on lipoprotein metabolism, resulting in better plasma lipid and apoprotein profiles.

Effects of long-term overfeeding on plasma lipoprotein levels in identical twins

Twelve pairs of male monozygotic (MZ) twins (mean age±S.D.: 21±2 years) were subjected to an overfeeding protocol of 4.2 MJ (1000 kcal) above their pre-established individual daily energy needs, 6 days a week, over a period of 100 days. Body weight increased significantly (gain of 8.1 kg, P<0.001), as did fat mass (5.4 kg, P<0.001) after overfeeding. Plasma triacylglycerol (TG) levels significantly increased ( P<0.05) without change in plasma cholesterol (CHOL). Plasma very-low-density-lipoprotein (VLDL)–TG, VLDL–Apoprotein (Apo) B, low-density-lipoprotein cholesterol (LDL-C) and LDL–Apo B ( P≤0.05) rose, whereas high-density-lipoprotein cholesterol (HDL-C) levels fell ( P<0.05) raising the CHOL/HDL-C ratio (20%) ( P<0.001). Considerable individual differences occurred in plasma lipoprotein responses to overfeeding. However, these changes were not random; significant within-pair resemblance registered for the response of plasma CHOL, TG, VLDL–TG, VLDL-C, LDL–TG, HDL-C, HDL–Apo A–I, HDL 2-C, HDL 3-C to overfeeding (0.48≤ r i ≤0.85). Furthermore, a high within-pair resemblance was found for changes in ratios of CHOL/HDL-C ( r i =0.86, P<0.0001) and HDL 2-C/HDL 3-C ( r i =0.69, P<0.01). These results strongly suggest that the response of plasma lipoproteins to chronic energy surplus has a significant genetic component as does the detrimental effect of chronic caloric affluence on CHD risk.

CSF taurine level is influenced by plasma cholesterol and the CYP2D6 phenotype

Eight healthy male volunteers, lumbar-punctured before and during simvastatin treatment, were phenotyped for CYP2D6 analysis of the debrisoquine metabolic ratio (the ratio between the urinary recovery of debrisoquine and its 4-hydroxy metabolite) after a single oral dose of debrisoquine. The mean cerebrospinal fluid concentrations of cholesterol and taurine did not differ before and during treatment. During (but not before) treatment taurine in the CSF correlated with the debrisoquine metabolic ratio ( r=−0.93; P=0.0007) Our results might indicate an influence of CYP2D6 on the level of taurine in the CSF that was secondary to the change in plasma cholesterol.

Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.

Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol.

Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer's disease (AD) in an isoform-dependent manner, such that the presence of the apoE epsilon4 allele increases the risk of AD while the presence of the apoE epsilon2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the "risk factor" activity of AD, its ability to bind amyloid beta peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Abeta accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer's amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.

THE EFFECTS OF SOYBEAN PROTEIN-DERIVED HYDROLYSATE ON LIPID METABOLISM IN RATS FED A HIGH CHOLESTEROL DIET

This study was performed to investigate the effects of the peptic undigested fraction derived from soybean protein hydrolysate (UDSP) on lipid metabolism in rats fed a cholesterol-enriched diet (1%). Eighteen male Wistar rats weighing 205-235 g were randomly divided into three groups: the control group (20% casein), U2 (18% casein + 2% UDSP), and U5 group (15% casein + 5% UDSP). After 4 weeks, rats were sacrificed, and the lipid profiles of the plasma, liver, and feces were determined. Body weight gain, daily food intake, and liver weight showed no differences among the groups, but the feeding efficiency ratio in the U5 group was significantly lower than that in the other groups (P < 0.05). There were no changes in plasma cholesterol, LDL-C, HDL-C, and liver cholesterol levels in each group. However, the U5 group showed a significantly lower VLDL-C compared to the control and U2 groups. In addition, the plasma and liver TG content were lower in the U2 and U5 groups than in the control group (P < 0. 05). Moreover, the fecal bile acid and total neutral steroid excretions were higher in the U2 and U5 groups (P < 0.05) compared to the control group.

Effect of atorvastatin on endothelium-dependent vasodilation in postmenopausal women with average serum cholesterol levels

After menopause, most healthy women show an impairment of peripheral vasodilation and an increase of plasma cholesterol levels. Statins have been shown to improve endothelial function in hypercholesterolemic men and women. The present study tests whether atorvastatin (10 mg) influences endothelium-dependent vasodilation in postmenopausal normocholesterolemic women. Twenty-eight healthy, postmenopausal women (mean age 51 ± 2 years) with serum total cholesterol and low-density lipoprotein cholesterol within the desirable range entered a double-blind, single-crossover study. Postmenopausal women were randomized to receive either atorvastatin (10 mg/day) or placebo for 10 days and then crossed to the complementary treatment. Endothelium-dependent and -independent responses were assessed by means of strain-gauge plethysmography before and after intra-arterial infusion of acethylcholine (ACh) and sodium nitroprusside, in comparison to physiologic saline. The nitric oxide pathway was evaluated by repeating the infusion of ACh during admininstration of l-arginine and (G)-monomethyl- l-arginine ( l-NMMA). Serum lipoproteins were not significantly modified by the active treatment. The vasodilation induced by ACh was significantly higher in the atorvastatin-treated women compared with the placebo-treated group (24 ± 3 vs 13 ± 2 ml/100 ml tissue/min, p <0.01). In contrast, responses to the endothelium-independent vasodilator sodium nitroprusside were not significantly modified by atorvastatin. The ACh-stimulated vasodilation induced by atorvastatin was additionally potentiated by l-arginine (800 ± 105% vs 370 ± 60%, p <0.05) and blunted by l-NMMA. No correlation was found between changes in plasma cholesterol and improvement in forearm blood flow. Our data show that the beneficial effect of atorvastatin on endothelium-dependent vasodilation is independent from changes in the lipid profile.

Cholesterol reduction following health screening in general practice

Objectives - To evaluate changes in plasma cholesterol following health screening and health discussions in general practice. Design - Randomised prospective population-based study conducted over a period of 5 years. Setting - Primary care, all general practitioners (GPs) in a welldefined area. Subjects - A random sample of inhabitants aged 30-49 years in January 1991, registered with a local GP was invited to participate. The participants (1507 persons, or 75.4% of the 2000 invited) were randomly allocated to two intervention groups and a control group. Main outcome measures - Plasma cholesterol, percentage of subjects with plasma cholesterol higher than 7 mmol/l. Results - After 5 years of intervention, plasma cholesterol in the whole population was significantly lower in the intervention groups compared to the control group. The decrease was most pronounced (0.5 mmol/l) in subjects at high cardiovascular risk. The percentage of high-risk individuals with a cholesterol level higher than 7 mmol/l was significantly lower in the intervention groups compared to the control group (9.8% vs 6.2%, p =0.04), corresponding to a 37% reduction. Conclusions - The study shows that the health checks had a measurable impact on plasma cholesterol levels, the most pronounced effect is seen among individuals at high cardiovascular risk.

Comparison of the antiatherosclerotic effect of tibolone with that of estradiol and ethinyl estradiol in cholesterol-fed, ovariectomized rabbits

Tibolone is a synthetic steroid with tissue-specific estrogenic, progestogenic, and androgenic properties. The drug relieves climacteric symptoms and prevents osteoporosis but does not stimulate the endometrium. We have previously shown that in laboratory animals tibolone inhibits the atherogenesis induced by a high-cholesterol diet. Therefore, we compared the antiatherosclerotic effect of oral tibolone at different dose levels with that of oral 17beta-estradiol (E2) and ethinyl estradiol (EE). Atherosclerotic lesion formation (increase in vessel wall cholesterol deposition and fatty streak formation) was measured in ovariectomized rabbits after 20 weeks on an atherogenic diet (fed daily 80 g of a rabbit chow containing 0.4% cholesterol, 3.75% peanut oil, and 3.75% coconut oil) in eight groups: group 1, placebo (n = 35); group 2, control (n = 34) received normal rabbit chow; group 3, E2 group (E2 4 mg, n = 12); group 4, EE group (EE 60 microg, n = 10); and groups 5-8, tibolone (6 mg, n = 12; 2 mg, n = 13; 0.6 mg, n = 25; and 0.15 mg, n = 11, respectively). During the study, blood samples were obtained for the evaluation of plasma triglycerides, cholesterol, lipoproteins, and glutamate pyruvate transaminase. After 20 weeks, the animals were killed, and cholesterol concentration and the formation of fatty streaks in the wall of the aortic arch were evaluated. In the placebo group, the atherogenic diet induced a mean increase in total plasma cholesterol concentration from 1.1+/-0.1 mmol/L (control group) to 34.1+/-1.8 mmol/L (mean +/- SE). This resulted in an accumulation of cholesterol in the aortic arch from 48+/-4 (control group) to 608+/-44 nmol/mg protein and in the formation of fatty streaks (41.8+/-3.2% of the surface of the aortic arch was covered with fatty streaks). Tibolone had strong dose-dependent antiatherosclerotic effects. It reduced the accumulation of cholesterol in the aortic arch at doses of 6 to 0.15 mg by 99, 97, 87, and 57% and the formation of fatty streaks by 98, 97, 81, and 38%, respectively. E2 had only a marginal antiatherosclerotic effect, whereas EE showed an effect comparable to that of tibolone at doses of 2 to 0.6 mg. With EE, the accumulation of cholesterol in the vessel wall was reduced by 93% and the formation of fatty streaks by 73%. Mean plasma cholesterol concentrations were also reduced by tibolone (64, 70, 61, and 47%) and EE (57%). This reduction was mainly mediated via a reduction in beta-very-low-density lipoprotein cholesterol. Analysis, however, indicated that the observed antiatherosclerotic effects of tibolone and EE, at least partly, are due to a direct effect on the vessel wall and independent of the changes in plasma cholesterol. At equipotent antiatherosclerotic doses, EE showed a stronger uterotropic effect (measured as the increase in uterine weight) than tibolone. EE increased uterine weight from 0.57 g/kg body weight (BW) (control group) to 3.5 g/kg BW; tibolone at doses of 6, 2, 0.6, and 0.15 mg increased uterine weight to 2.5, 2.8, 2.2, and 1.3 g/kg BW, respectively. Tibolone can protect the arterial vessel wall against atherosclerotic lesions induced by a hypercholesterolemic diet. However, it has much less estrogenic effects on the uterus compared with EE at equipotent doses, indicating tissue selectivity for tibolone. The clinical implications of these findings require investigation.

Validity and Reliability of Qualitative Dietary Fat Index Questionnaires: A Review

Traditional methods for assessing dietary behavior such as 24-hour dietary recalls, diet records, and food frequency questionnaires may not measure what we want to know about dietary behaviors of a population. Moreover, their usefulness is often limited in nutrition interventions because of cost, respondent burden, bias, and staff requirements ( (1) Kristal A.R. Shattuck A.L. Henry H.J. Patterns of dietary behavior associated with selecting diets low in fat reliability and validity of a behavioral approach to dietary assessment. J Am Diet Assoc. 1990; 90: 214-220 Google Scholar , (2) Kristal A.R. Shattuck A.L. Henry H.J. Fowler A.S. Rapid assessment of dietary intake of fat, fiber, and saturated fat validity of an instrument suitable for community intervention research and nutritional surveillance. Am J Health Promotion. 1990; 4: 288-295 Google Scholar , (3) Gray-Donald K. J O.L. Richard L. Paradis G. Validation of a short telephone administered questionnaire to evaluate dietary interventions in low income communities in Montreal, Canada. J Epidemiol Community Health. 1997; 51: 326-331 Google Scholar , (4) Connor S.L. Gustafson J.R. Sexton G. Becker N. Artaud-Wild S. Connor W.E. The Diet Habit Survey a new method of dietary assessment that relates to plasma cholesterol changes. J Am Diet Assoc. 1992; 92: 41-47 Google Scholar , (5) Gans K.M. Sundaram S.G. McPhillips J.B. Hixson M.L. Linnan L. Carelton R.A. Rate Your Plate an eating assessment and education tool used at cholesterol screening and education programs. J Nutr Educ. 1993; 25: 29-35 Google Scholar , (6) Ammerman A.S. Haines P.S. DeVellis R.F. Strogatz D.S. Keyserling T.C. Simpson Jr., R.J. Siscovick D.S. A brief dietary assessment to guide cholesterol reduction in low-income individuals design and validation. J Am Diet Assoc. 1991; 91: 1385-1390 Google Scholar , (7) Glasgow R.E. Perry J.D. Toobert D.J. Hollis J.F. Brief assessments of dietary behavior in field settings. Addict Behav. 1996; 21: 239-247 Google Scholar ). As an alternative, qualitative dietary fat index questionnaires (QFQs) have been developed to assess dietary behavior. This project was funded, in part, by the National Foundation for the Centers for Disease Control and Prevention. The authors thank Mary Serdula, MD, for her suggestions and commentary on an earlier version of this manuscript.

Plasma Carotenoids Are Biomarkers of Long-Term High Vegetable Intake in Women with Breast Cancer

We investigated predictors of change in plasma carotenoids from baseline to 3 y and examined plasma carotenoid concentrations at 1 and 3 y in response to a high vegetable diet. Participants were 56 women diagnosed with breast cancer and enrolled in a randomized feasibility study for a trial examining the effect of a diet high in vegetables and fruits on the risk of breast cancer recurrence. Independent t test analysis revealed that the intervention group had significantly higher vegetable and fruit servings and fiber at 12 mo and significantly higher vegetable servings at 36 mo compared with the control group (P < 0.05). Energy intake from fat was significantly lower in the intervention group at 12 and 36 mo. The intervention group had significantly higher consumption of β-carotene, α-carotene, lutein and β-cryptoxanthin at 12 mo (P < 0.05). β-Carotene, α-carotene and lutein intakes also were significantly higher at 36 mo (P < 0.05). At 36 mo, the intervention group had significantly higher plasma concentrations of α-carotene and β-carotene compared with the control group. Repeated-measures ANOVA revealed that the intervention group had significantly increased (P < 0.05 with Bonferroni correction) plasma β-carotene, α-carotene, lutein and lycopene concentrations at 12 and 36 mo compared with baseline. Baseline carotenoid concentrations were significantly inversely predictive (P < 0.05) of plasma carotenoid change. In addition, change in body mass index (BMI) and plasma cholesterol concentrations were predictive of plasma carotenoid change from baseline to 3 y. Results of this study demonstrate that change in plasma carotenoid concentrations is associated with change in BMI, change in plasma cholesterol and baseline carotenoid concentrations. Plasma carotenoid response can be an indicator of long-term high vegetable intake for women at risk of breast cancer recurrence.

Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice

Lipoprotein lipase (LPL) is known to play a crucial role in lipoprotein metabolism by hydrolyzing triglycerides; however its role in atherogenesis has yet to be determined. We have previously shown that low density lipoprotein receptor knockout mice overexpressing LPL are resistant to diet-induced atherosclerosis due to the suppression of remnant lipoproteins. Plasma lipoproteins and atherosclerosis of apolipoprotein (apo) E knockout mice which overexpress the human LPL transgene (LPL/APOEKO) were compared with those of control apoE knockout mice (APOEKO). On a normal chow diet, LPL/APOEKO mice showed marked suppression of the plasma triglyceride levels compared with APOEKO mice (54 vs. 182 mg/dl), but no significant changes in plasma cholesterol and apoB levels. Non-high density lipoproteins (HDL) from LPL/APOEKO mice had lower triglyceride content, a smaller size, and a more positive charge compared with those from APOEKO mice. Cholesterol, apoA-I, and apoA-IV were increased in HDL. Although both groups developed hypercholesterolemia to a comparable degree in response to an atherogenic diet, the LPL/APOEKO mice developed 2-fold smaller fatty streak lesions in the aortic sinus compared to the APOEKO mice.▪In conclusion, overproduction of LPL is protective against atherosclerosis even in the absence of apoE.—Yagyu, H., S. Ishibashi, Z. Chen, J. Osuga, M. Okazaki, S. Perrey, T. Kitamine, M. Shimada, K. Ohashi, K. Harada, F. Shionoiri, N. Yahagi, T. Gotoda, Y. Yazaki, and N. Yamada. Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice. J. Lipid Res. 1999. 40: 1677–1685.

Short-Chain Fatty Acids Suppress Cholesterol Synthesis in Rat Liver and Intestine

We previously showed that plasma cholesterol levels decreased following ingestion of a short-chain fatty acid (SCFA) mixture composed of sodium salts of acetic, propionic, and butyric acids simulating cecal fermentation products of sugar-beet fiber (SBF). In the present study, we investigated whether hepatic and small intestinal cholesterol synthesis is involved in the cholesterol-lowering effects of SCFA and SBF. In vitro (expt. 1) and in vivo (expt. 2) cholesterol synthesis rates and the diurnal pattern of SCFA concentrations in portal plasma (expt. 3) were studied in three separate experiments in rats fed diets containing the SCFA mixture, SBF (100 g/kg diet), or the fiber-free control diet. Cholesterol synthesis was measured using 3H2O as a tracer. The in vitro rate of cholesterol synthesis, measured using liver slices, was greater in the SBF group, but not in the SCFA group, than in the fiber-free control group. In contrast, the hepatic cholesterol synthesis rate in vivo was lower in the SCFA group, but not in the SBF group, than in the control group. The mucosal cholesterol synthesis rate for the whole small intestine was <50% of the hepatic rate. The rate in the proximal region was slightly but significantly lower in the SCFA group, and was significantly higher in the SBF group than in the fiber-free group. The rate in the distal small intestines was also significantly greater in the SBF group than in the fiber-free group. Plasma total cholesterol concentrations were lower in the SCFA and SBF groups than in the fiber-free group in both experiments 2 and 3. Diurnal changes in portal SCFA and cholesterol levels were studied in the experiment 3. SCFA concentrations increased rapidly after the start of feeding the SCFA diet, and changes in plasma cholesterol were the reciprocal of those observed in SCFA. These results show that a decrease in hepatic cholesterol synthesis rate mainly contributes to the lowering of plasma cholesterol in rats fed the SCFA mixture diet. Changes in portal SCFA and cholesterol concentrations support this conclusion. In SBF-fed rats, SCFA produced by cecal fermentation are possibly involved in lowering plasma cholesterol levels by negating the counteractive induction of hepatic cholesterol synthesis caused by an increase in bile acid excretion.

Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse

Acute inflammation results in a profound change in the apolipoprotein composition of high density lipoprotein (HDL). Several isoforms of the serum amyloid A (SAA) family, SAA 1 and SAA 2, become major components of HDL. This structural relationship has suggested that acute phase SAA plays some as yet unidentified role in HDL function, possibly related to cholesterol transport, during the course of acute inflammation. Using subcutaneous AgNO 3 to induce a sterile abscess changes in plasma cholesterol and SAA were monitored over the subsequent 144 h. Total plasma cholesterol began to increase within 12 h of the induction of inflammation and reached a peak in 24 h. Thereafter its plasma levels fell returning to normal values by 96–120 h. The bulk of the increase in plasma cholesterol was found in the free cholesterol fraction of HDL. This pattern of cholesterol increase corresponds to the established temporal changes for acute phase SAA (AP-SAA). AP-SAA levels increased within 8 h of the induction of inflammation and reached a peak at 24 h. They began to decrease by 48 h with small quantites still present 120 h later. In concert, but inversely, with the changes in AP-SAA the apoA-I, apoA-II, and apo-E, content of HDL decreased during the AP-SAA increases and increased as AP-SAA levels fell. The plasma appearance of cholesterol from the periphery, and central parts of the inflammatory site was assessed by the use of radiolabelled cholesterol. The peripherally placed cholesterol rapidly reached a peak plasma concentration within 24 h of injection. Cholesterol placed in the central part of the sterile abscess, a site relatively inaccessible to the vasculature required 48 h to reach its peak and was 5-times lower than that placed peripherally. The influence of AP-SAA on neutral cholesterol ester hydrolase (nCEH) activity in mouse liver homogenates, mouse peritoneal macrophage homogenates, and a purified porcine pancreatic enzyme with nCEH activity was also assessed. Following optimization with regard to pH, bile salt concentration, protein concentration and incubation time, mouse peritoneal macrophages had a significantly higher nCEH specific activity than that found in liver (7–8 fold). Purified AP-SAA, assessed over a concentration range of 0–10 μg/ml, enhanced nCEH activity at concentrations above 2 μg/ml. The nCEH activity, regardless of its source, increased by 3–7 fold in the presence of AP-SAA. Equivalent concentrations of apolipoprotein A-I (apo A-I) and bovine serum albumin (BSA) failed to alter the activity of nCEH. The effect of AP-SAA on a purified form of nCEH suggests that AP-SAA may have a direct effect on the activity of this enzyme. The temporal correlation of circulating AP-SAA and plasma cholesterol and the significant stimulation of nCEH by AP-SAA (but not apoA-I or BSA) provides further evidence that AP-SAA plays a role in cholesterol metabolism during the course of acute inflammation.

Method issues in dietary data analyses in the Multiple Risk Factor Intervention Trial

The selection process in the Multiple Risk Factor Intervention Trial caused relations between risk factors to differ between participants who were randomly assigned into the study and the screening population. Cigarette smoking, blood pressure, and serum cholesterol were moderately inversely related to each other in the randomly assigned population whereas these relations in the unselected population were direct and small in magnitude. This problem was addressed by covariate adjustment in analyses. The selection process also created an artificially high initial mean concentration of serum cholesterol; the mean plasma concentration at the second screening was 15 mg/dL lower than at the first screening. Most of this difference is attributable to regression to the mean. To account for this problem, emphasis was placed on change in plasma cholesterol over time, calculated from the second-screening measurement. Examination of the reliability of nutrition data based on one 24-h dietary recall showed that nutrient-biochemical relations are subject to considerable regression-dilution bias. The ratios of "within" to "between" components of variability were typically between one and four. Analyses in which multiple follow-up measures were averaged are emphasized in this monograph. Men assigned to the special intervention group reported considerable reductions in total energy intake, which was not consistent with observed weight loss. The most likely explanation for this is underreporting or underconsumption the day before the recall. To partially adjust for this, nutrient data are often expressed both in absolute units and as nutrient densities.

Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice.

We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow- and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-beta-estradiol pellets releasing either 6, 14, or 28 micrograms/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-alpha-estradiol (28 micrograms/day) or tamoxifen (85 micrograms/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-beta-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels.

Dietary cholesterol and the optimal diet for reducing risk of atherosclerosis: D.J. McNamara. Lipid Metabolism Laboratory, University of Arizona, Tuczon, AZ. Can J Cardiol 1995;11(Suppl. G):123G–6G

The importance of dietary cholesterol in the incidence of hypercholesterolemia in the population remains a topic of scientific debate. Analysis of the results from over 30 years of cholesterol feeding studies (n = 128) in more than 2750 patients indicate that for the majority of individuals modest changes in dietary cholesterol have little if any effect on plasma lipoprotein cholesterol levels. Data demonstrate that on average a change in cholesterol intake of 100 mg/day results in a change in plasma total cholesterol of 0.07 mmol/L (2.5 mg/dL). The studies also show that the extent of response to dietary cholesterol is independent of the amount of dietary fat and of the baseline plasma cholesterol level. In contrast, the dose adjusted plasma cholesterol response to a dietary cholesterol challenge is affected by the type of dietary fat and the baseline dietary cholesterol intake. Based on these data a reduction in dietary cholesterol intake from 450 to 300 mg/day will, on average, lower plasma cholesterol levels by 0.10 mmol/L (3.7 mg/dL). This decrease is modest and highly variable due to significant interindividual heterogeneity of responses. It is estimated that one-third of the population is sensitive to dietary cholesterol whereas two-thirds are resistant to plasma cholesterol changes. In comparison, a 1% decrease in energy intake from saturated fat decreases plasma cholesterol 0.08 mmol/L (3 mg/dL). Consumption of products marketed as 'No cholesterol' with high total and saturated fat clearly does not contribute to the optimal diet for reducing plasma cholesterol levels of risk of atherosclerosis.

Laser aggregometer studies, ATP release and thromboxane B2 release and cAMP concentration of the platelets in nephrotic syndrome

Platelet function was studied in 56 children with nephrotic syndrome, 33 were on oral prednisolone (P) treatment (group 1), while 23 were in early (< 6 months) remission (group 2): 12 on P (group 2a) and 11 not on P (group 2b), and there were 18 controls (group 3). The following tests were used: platelet aggregation with collagen in a laser rheoaggregometer; adenosine triphosphate (ATP) release: during aggregation with luciferin-luciferase in a lumiaggregometer; thromboxane B2 (TXB2) release: by radio-immunoassay; platelet cAMP concentration: by binding assay. The changes in plasma cholesterol (C) and triglycerides (TG) were compared with the platelet aggregation results. Patients in group 1 and 2 exhibited significantly higher aggregability, TXB2 release and ATP release in response to collagen than those in group 3 (p < 0.01), but there was no difference between groups 1 and 2 or groups 2a and 2b. Some differences were observed between the histological groups. Patients with IgA and SLE nephropathy displayed higher aggregability than those with minimal change nephrotic syndrome in remission (p < 0.05). The highest level was in membranous nephropathy. The platelet cyclic adenosine monophosphate (cAMP) concentration was significantly lower in groups 1 and 2 than in group 3 (p < 0.001). No differences were observed between groups 1 and 2 or between groups 2a and 2b. Plasma C and TG levels did not show any correlation with the platelet aggregation. The increased platelet aggregation, TXB2 release and ATP release and decreased cAMP concentration in the platelets may play a role in the pathogenesis of nephrotic syndrome which remains altered in early remission. Oral P and plasma lipids did not change the platelet function significantly.