We studied the effects of 20 weeks of supervised cycle-ergometer exercise on plasma lipids in 675 healthy, sedentary, normolipidemic white and black men and women aged 17 to 65 years, participating in the HERITAGE Family Study. Fasting plasma lipids were assessed twice at baseline and 24 and 72 hours after the last exercise session and adjusted for plasma volume changes. No significant differences from the mean baseline levels were observed for total, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B (Apo B). A significant reduction (P < .01) from baseline levels in plasma total and VLDL triglycerides was observed only in the 24-hour posttraining specimens, reflecting a response to the last bout of exercise. High-density lipoprotein (HDL) cholesterol increased 3.6% for the combined group, primarily due to an increase in HDL2, with an associated increase in Apo A-1 (P < .001). No significant differences were noted in the HDL response by sex, race, or age. An inverse correlation (r = -.241) was observed between the increase in HDL cholesterol and change in body fat only in men, and the increase in HDL cholesterol was unrelated to the change in maximal oxygen uptake (VO2max).

A low HDL-cholesterol concentration is an independent risk factor for CVD. Studies have suggested that flavonoid consumption may be cardioprotective, and a favourable impact on circulating HDL-cholesterol concentrations has been suggested to partially explain this association. The aim of the present study was to determine the effect of consuming increasing daily doses of low-calorie cranberry juice cocktail (CJC) on the plasma lipid profile of abdominally obese men. For that purpose, thirty men (mean age 51 (SD 10) years) consumed increasing doses of CJC during three successive periods of 4 weeks (125 ml/d, 250 ml/d, 500 ml/d). Before the study and after each phase, we measured changes in physical and metabolic variables. We noted a significant increase in plasma HDL-cholesterol concentration after the consumption of 250 ml CJC/d (+8.6+/-14.0% v. 0 ml CJC/d; P<0.01), an effect that plateaued during the last phase of the study (500 ml CJC/d: +8.1+/-10.0% v. 0 ml CJC/d; P<0.0001). Multivariate analyses revealed that changes in plasma apo A-I (R(2)=48%, P<0.0001) and triacylglycerol (R(2)=16%, P<0.005) concentrations were the only variables significantly contributing to the variation in plasma HDL-cholesterol concentration noted in response to the intervention. No variation was observed in total as well as in LDL and VLDL cholesterol. The present results show that daily CJC consumption is associated with an increase in plasma HDL-cholesterol concentrations in abdominally obese men. We hypothesise that polyphenolic compounds from cranberries may be responsible for this effect, supporting the notion that the consumption of flavonoid-rich foods can be cardioprotective.

Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.

We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.

Hepatic expression of ChREBP-β and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-β and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.

In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

Five subjects ingested in a single oral dose containing 50 mg each of 2R,4'R,8'R-alpha-(5,7-(C2H3)2)tocopheryl acetate (d6-RRR-alpha-tocopheryl acetate) with natural stereochemistry, and of 2S,4'R,8'R-alpha-(5-C2H3)tocopheryl acetate (d3-SRR-alpha-tocopheryl acetate). These are two of eight stereoisomers in synthetic vitamin E. By day 1 the plasma and red blood cells were enriched fourfold with d6-RRR-alpha-tocopherol (P less than 0.004). The ratio of d6-RRR-/d2-SRR- further increased over the succeeding 4 days, because the d3-SRR- decreased at a faster rate than did the d6-RRR-stereoisomer. Plasma and lipoproteins were isolated at intervals during the first day, and daily for 3 days, from four additional subjects fed a mixture of equal amounts of the deuterated tocopherols. The plasma contained similar concentrations of the two forms until 11 h, when the d6-RRR-alpha-tocopherol concentration became significantly greater (P less than 0.05). The chylomicrons contained similar concentrations of the two deuterated tocopherols, but the VLDL (very low density lipoproteins) became preferentially enriched in d6-RRR-alpha-tocopherol by 11 h. The pattern of the deuterated tocopherols shows that during chylomicron catabolism all of the plasma lipoproteins were labeled equally with both tocopherols, but that during the subsequent VLDL catabolism the low and high density lipoproteins became enriched in d6-RRR-alpha-tocopherol. These results suggest the existence of a mechanism in the liver for assembling VLDL preferentially enriched in RRR- relative to SRR-alpha-tocopherol.

Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are responsible for the esterification of cell-derived cholesterol and for the transfer of newly synthesized cholesteryl esters (CE) from HDL to apoB-containing lipoproteins in human plasma. LCAT and CETP are also crucial factors in HDL remodeling, a process by which HDL particles with a high capacity for cell cholesterol uptake are generated in plasma. In the present study, cholesterol esterification and transfer were evaluated in 60 patients with isolated hypercholesterolemia (HC, n = 20) and isolated (HTG, n = 20) or mixed hypertriglyceridemia (MHTG, n = 20) and in 20 normolipidemic healthy individuals (NL). Cholesterol esterification rate (CER) and net CE transfer rate (CETR) were measured in whole plasma. LCAT and CETP concentrations were determined by specific immunoassays. HDL remodeling was analyzed by monitoring changes in HDL particle size distribution during incubation of whole plasma at 37 degrees C. Mean CER and CETR were 48% and 73% higher, respectively, in hypertriglyceridemic (HTG + MHTG) versus normotriglyceridemic individuals. HDL remodeling was also significantly accelerated in plasma from hypertriglyceridemic patients. Strong positive correlations were found in the total sample between plasma and VLDL triglyceride levels and CER (r = .722 and r = .642, respectively), CETR (r = .510 and r = .491, respectively), and HDL remodeling (r = .625 and r = .620, respectively). No differences in plasma LCAT and CETP concentrations were found among the various groups except for a tendency toward higher CETP levels in hypercholesterolemic patients (+51% in MHTG and +20% in HC) versus control subjects (NL). By stepwise regression analysis, VLDL triglyceride level was the sole significant predictor of CER and CETR and contributed significantly together with baseline HDL particle distribution to HDL remodeling. These results indicate that plasma triglyceride level is a major factor in the regulation of cholesterol esterification/transfer and HDL remodeling in human plasma, whereas LCAT/CETP concentrations play a minor role in the modulation of reverse cholesterol transport.

OBJECTIVE

To additionally test validity of the recently developed method (LDL baseline diene conjugation, LDL-BDC) for determination of circulating oxidized LDL.

METHODS

A detailed comparison between the ultracentrifugation and heparin precipitation methods for LDL isolation was performed to test suitability of the fast precipitation method. Validity of LDL-BDC as an indicator of circulating oxidized LDL was tested by comparing LDL-BDC to results obtained by the immunological autoantibody method.

RESULTS

BDC values in LDL isolated by heparin precipitation did not differ from those isolated by sequential ultracentrifugation. While highest amount of diene conjugation was found in LDL (40% of that in serum), substantial amounts were also found in VLDL (31%) and HDL (25%). When analyzed in the same samples, assays for the titer of autoantibodies against oxidized LDL and LDL-BDC were found to show good correlation (r = 0.57, p = 0.001, n = 29).

CONCLUSIONS

These results, together with thus far conducted studies on clinical applicability of the method, indicate that LDL-BDC is a promising candidate in search for a method for estimation of LDL oxidation in vivo.

OBJECTIVE

The purpose of this study was to examine the effect of weight loss on LDL and HDL kinetics and plasma retinol-binding protein-4 (RBP-4) and adiponectin levels in men with the metabolic syndrome.

METHODS

LDL apolipoprotein (apo)B-100 and HDL apoA-I kinetics were studied in 35 obese men with the metabolic syndrome at the start and end of a 16-week intervention trial of a hypocaloric, low-fat diet (n = 20) versus a weight maintenance diet (n = 15) using a stable isotope technique and multicompartmental modeling.

RESULTS

Consumption of the low-fat diet produced significant reductions (P < 0.01) in BMI, abdominal fat compartments, and homeostasis model assessment score compared with weight maintenance. These were associated with a significant increase in adiponectin and a fall in plasma RBP-4, triglycerides, LDL cholesterol, and LDL apoB-100 concentration (P < 0.05). Weight loss significantly increased the catabolism of LDL apoB-100 (+27%, P < 0.05) but did not affect production; it also decreased both the catabolic (-13%) and production (-13%) rates of HDL apoA-I (P < 0.05), thereby not altering plasma HDL apoA-I or HDL cholesterol concentrations. VLDL apoB-100 production fell significantly with weight loss (P < 0.05). The increase in LDL catabolism was inversely correlated with the fall in RBP-4 (r = -0.54, P < 0.05) and the decrease in HDL catabolism with the rise in adiponectin (r = -0.56, P < 0.01).

CONCLUSIONS

In obese men with metabolic syndrome, weight loss with a low-fat diet decreases the plasma LDL apoB-100 concentration by increasing the catabolism of LDL apoB-100; weight loss also delays the catabolism of HDL apoA-I with a concomitant reduction in the secretion of HDL apoA-I. These effects of weight loss could partly involve changes in RBP-4 and adiponectin levels.

BACKGROUND

Quercetin plays a cardiovascular protective role because of its antioxidant capacity and ability to modulate dyslipidemia. As alterations in hepatic lipid synthesis are crucial to the regulation of serum lipid levels, we investigated the quercetin effect on lipogenesis in rat liver cells.

METHODS

The effect of quercetin on the rate of synthesis of fatty acids, cholesterol, neutral lipids, phospholipids and very-low-density lipoproteins (VLDL) was investigated in rat hepatocyte suspensions following [1-(14)C]acetate incorporation into these lipid fractions. Enzyme activities of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) as well as diacylglycerol acyltransferase (DGAT) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-R), pace-setting steps of de novo fatty acid, triacylglycerol (TAG) and cholesterol synthesis respectively were assayed in digitonin-permeabilized hepatocytes.

RESULTS

Within 30 min of quercetin addition to the hepatocytes, inhibition (IC50 approximately 25 microM) of fatty acid synthesis occurred. A reduction in label incorporation mainly into TAG was observed. Among neosynthesized fatty acids, palmitic acid formation was greatly reduced, suggesting that enzymatic step(s) of de novo fatty synthesis was affected. Only ACC activity was noticeably reduced, but no change in FAS activity was observed. DGAT activity was also inhibited. The decreased intracellular TAG content was paralleled by a reduction in acetate incorporation into VLDL-TAG. Conversely, cholesterol synthesis and HMG-CoA-R were not significantly affected by quercetin.

CONCLUSIONS

In hepatocytes from normal rats, the quercetin-induced decrease in both de novo fatty acid and TAG synthesis, with a consequent reduction in VLDL-TAG formation, may represent a potential mechanism contributing to the reported hypotriacylglycerolemic effect of quercetin.

The effects of variations in dietary carbohydrate and fat on various aspects of carbohydrate and lipoprotein metabolism were evaluated in 10 healthy, postmenopausal women. The two diets were isoenergetic, assigned in random fashion, and consisted (as a % of total energy) of 15% protein, 60% carbohydrate, and 25% fat (60%-carbohydrate diet) or 15% protein, 40% carbohydrate, and 45% fat (40%-carbohydrate diet). Fasting plasma triacylglycerol, very-low-density-lipoprotein (VLDL) triacylglycerol, and VLDL-cholesterol concentrations were higher (P < 0.05-0.001) after the 60%-carbohydrate diet, whereas high-density-lipoprotein (HDL) cholesterol was lower (P < 0.05). Plasma insulin and triacylglycerol concentrations were also higher (P < 0.001) from 0800 to 0000 with the 60%-carbohydrate diet than with the 40%-carbohydrate diet. In addition, when vitamin A was given with the noon meal, the ensuing concentrations of retinyl palmitate were also higher after ingestion of the 60%-carbohydrate diet. Resistance to insulin-mediated glucose disposal, quantified at baseline by determining the steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of somatostatin, insulin, and glucose, correlated with the incremental increases in postprandial concentrations of plasma glucose (r = 0.68, P = 0.06), insulin (r = 0.82, P < 0.02), triacylglycerol (r = 0.77, P < 0.05), and retinyl palmitate (r = 0.68, P = 0.06) and with the Sf>> 400 triacylglycerol (r = 0.77, P < 0.05), Sf 20-400 triacylglycerol (r = 0.72, P < 0.05), and Sf>> 400 retinyl palmitate (r = 0.75, P < 0.01) lipoprotein fractions. Because all of these changes would increase risk of ischemic heart disease in postmenopausal women, it seems reasonable to question the wisdom of recommending that postmenopausal women consume low-fat, high-carbohydrate diets.

It has been suggested that lung function can be altered by both free radical and oxidant exposure, while antioxidant vitamin intake is positively related to lung function. However, the information on the relation of blood levels of oxidants and antioxidants to lung function is sparse. The present cross-sectional study, conducted from September 1995 to May 1996, analyzes the association between lung function measured as forced expiratory volume in 1 second (FEV1) with 1) levels of thiobarbituric acid-reactive substances in plasma (p-TBARS) and in low and very low density lipoprotein cholesterol (LDL cholesterol/VLDL cholesterol-TBARS) as indicators of lipid peroxidation and 2) compounds with antioxidant activity, erythrocytic glutathione, plasma glutathione peroxidase, trolox equivalent antioxidant capacity, and serum bilirubin, which may protect against lipid peroxidation. The analysis was carried out in 132 nonsmoking subjects aged 37-73 years who were randomly selected from the residents of Erie and Niagara counties, New York. FEV1 in percent of the predicted value (FEV1%) was negatively and statistical significantly associated with p-TBARS (r = -0.19). A negative association with borderline statistical significance was observed between FEV1% with low density lipoprotein cholesterol/very low density lipoprotein cholesterol-TBARS (r = -0.16) and glutathione (r = -0.16), while FEV1% was positively related to serum bilirubin (r = 0.15). Participants in the lowest quartile of FEV1% showed significantly higher levels of p-TBARS (p = 0.02) and lower levels of bilirubin (p = 0.04) than did those in the highest quartile. Our results suggest that increased lipid peroxidation is associated with pulmonary airway narrowing in the general population.

Appearance, pharmacokinetics, and distribution of astaxanthin E/Z and R/S isomers in plasma and lipoprotein fractions were studied in 3 middle-aged male volunteers (37-43 years) after ingestion of a single meal containing a 100 mg dose of astaxanthin. The astaxanthin source consisted of 74% all-E-, 9% 9Z-, 17% 13Z-astaxanthin (3R,3'R-, 3R,3'S; meso-, and 3S,3'S-astaxanthin in a 1:2:1 ratio). The plasma astaxanthin concentration--time curves were measured during 72 hr. Maximum levels of astaxanthin (1.3 +/- 0.1 mg/L) were reached 6.7 +/- 1.2 hr after administration, and the plasma astaxanthin elimination half-life was 21 +/- 11 hr. 13Z-Astaxanthin accumulated selectively, whereas the 3 and 3'R/S astaxanthin distribution was similar to that of the experimental meal. Astaxanthin was present mainly in very low-density lipoproteins containing chylomicrons (VLDL/CM; 36-64% of total astaxanthin), whereas low-density lipoprotein (LDL) and high-density lipoprotein (HDL) contained 29% and 24% of total astaxanthin, respectively. The astaxanthin isomer distribution in plasma, VLDL/CM, LDL, and HDL was not affected by time. The results indicate that a selective process increases the relative proportion of astaxanthin Z-isomers compared to the all-E-astaxanthin during blood uptake and that astaxanthin E/Z isomers have similar pharmacokinetics.

OBJECTIVE

To investigate the mechanisms by which bezafibrate retarded the progression of coronary lesions in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), we examined the relationships of on-trial lipoproteins and lipoprotein subfractions to the angiographic outcome measurements.

BACKGROUND

BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment.

METHODS

A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography.

RESULTS

In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (-53%) and triglyceride (-46%) and plasma apolipoprotein (apo) B (-9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL3) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +032 nm). The on-trial HDL3 cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r=-0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression.

CONCLUSIONS

Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.

Familial combined hyperlipidemia (FCHL) may be genetically and metabolically more heterogeneous than previously thought. A consistent feature is an increase in circulating very-low-density lipoprotein (VLDL) apolipoprotein (apo) B, which could be due to either an increase in apoB production or a decrease in its catabolism. Therefore, we directly measured VLDL apoB production in the postabsorptive state in seven FCHL subjects (four male, three female) and seven normal control subjects (three male, four female) by using L-[1-13C]leucine as an endogenous label. Mean age and body mass index did not differ significantly between the two groups. The mean total cholesterol levels were 4.7 +/- 0.8 and 8.8 +/- 1.6 mmol/L (+/- SD, P < .01) and the mean triglyceride levels were 0.84 +/- 0.14 and 3.30 +/- 1.10 mmol/L (+/- SD, P < .01) in the control and FCHL groups, respectively. Although the fractional production rate of VLDL apoB was 38% lower in the FCHL group than in the control subjects (0.11 +/- 0.03 versus 0.18 +/- 0.02 pool/h; mean +/- SD, P < .01), its absolute production rate was 2.7 times greater (534 +/- 193 micrograms/kg per hour in FCHL versus 196 +/- 71 micrograms/kg per hour in control subjects; mean +/- SD, P < .01). There was a linear relation (r = 0.8, P = .03) between triglyceride levels and the VLDL apoB production rate in FCHL, the slope of which indicated a similar VLDL triglyceride-to-apoB ratio in the FCHL and control groups. We conclude that FCHL is a metabolically coherent disorder and that the increase in circulating apoB and triglyceride levels in FCHL is due to secretion of an increased number of VLDL particles, each containing, on average, a normal amount of triglyceride and one molecule of apoB.(ABSTRACT TRUNCATED AT 250 WORDS)

We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5 +/- 2.2 years (mean +/- SEM), weight 88.2 +/- 5.5 kg, glycated haemoglobin (HbA1) 8.5 +/- 0.5%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 3.8 +/- 0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0 +/- 0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7 +/- 2.8 years, weight 85.8 +/- 5.6 kg, HbA1 6.5 +/- 0.1%, plasma total cholesterol concentration 5.7 +/- 0.5 mmol/l, triglyceride 1.2 +/- 0.1 mmol/l, HDL cholesterol 1.4 +/- 0.1 mmol/l). HbA1, plasma triglyceride and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects (p = 0.006, p = 0.02 and p = 0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297 +/- 491 vs 921 +/- 115 mg/day, p < 0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide (r = 0.84, p = 0.04) and (ii) mevalonic acid concentration (r = 0.83, p < 0.05) in the diabetic patients but not in the non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

We investigated the associations between plasma very-low-density lipoprotein (VLDL)-apolipoprotein (apo)C-III and apoA-V concentrations and the kinetics of VLDL-apoB-100 and VLDL triglycerides in 15 men. We also explored the relationship between these parameters of VLDL metabolism and VLDL-apoC-III kinetics.

RESULTS

ApoC-III, apoB, and triglyceride kinetics in VLDL were determined using stable isotopes and multicompartmental modeling to estimate production rate (PR) and fractional catabolic rate (FCR). Plasma VLDL-apoC-III concentration was significantly and inversely associated with the FCRs of VLDL triglycerides (r=-0.610) and VLDL-apoB (r=-0.791), and positively correlated with the PR of VLDL-apoC-III (r=0.842). However, apoA-V concentration was not significantly associated with any of the kinetic variables. There was a significant association (P<0.01) between the PRs of VLDL triglycerides and VLDL-apoB (r=0.641), and between the FCRs of VLDL triglycerides and VLDL-apoB (r=0.737). In multiple regression analysis, plasma VLDL-apoC-III concentration was a significant predictor of VLDL triglyceride FCR (beta-coefficient=-0.575) and VLDL-apoB FCR (beta-coefficient=-0.839).

CONCLUSIONS

Our findings suggest that increased VLDL-apoC-III concentrations resulting from an overproduction of VLDL-apoC-III are strongly associated with the delayed catabolism of triglycerides and apoB in VLDL. We also demonstrated that the kinetics of VLDL triglycerides and apoB are closely coupled. Our data do not support a role for plasma apoA-V in regulating VLDL kinetics.

The hepatitis C virus (HCV) requires elements of host lipid metabolism for every step in the viral life cycle. Clinically, it has long been observed that patients with chronic hepatitis C have lower nonhigh-density lipoprotein cholesterol, and these levels rise after successful treatment. The HCV itself circulates as a highly lipidated lipoviral particle, which closely resembles very low-density lipoprotein (VLDL). Several required coentry factors for the virus to gain access to the hepatocytes have been described, and several, including SRB1, LDL-R, and the NPC1L1 receptors, are important receptors for lipoprotein and cholesterol uptake. Inside the cell, the virus induces lipogenesis, and specifically induces the master regulator sterol response element binding protein. Viral replication then requires the concerted efforts of viral proteins combined with several host factors involved in cholesterol synthesis. The virus is then packaged alongside the cellular machinery for VLDL production. The complex interplay highlights pathways of hepatic steatosis and unveils drug targets for the treatment of HCV.

To determine the effects of carbohydrate restriction (CR) with and without soluble fiber on lipoprotein metabolism, 29 men participated in a 12-wk weight loss intervention. Subjects were matched by age and BMI and randomly assigned to consume 3 g/d of either a soluble fiber supplement (n=14) or placebo (n=15) with a macronutrient energy distribution of approximately 10% carbohydrate, approximately 65% fat, and approximately 25% protein. Because the groups did not differ in any of the variables measured, all data were pooled and comparisons were made between baseline and 12 wk. After 12 wk, subjects had a mean weight loss of 7.5 kg (P<0.001), and abdominal fat was reduced by 20% (P<0.001). Plasma LDL cholesterol and triglycerides (TG) were significantly reduced by 8.9 and 38.6%, respectively. Similarly, apolipoproteins C-I (-13.8%), C-III (-21.2%) and E (-12.5%) were significantly lower after the intervention. In contrast plasma HDL-cholesterol concentrations were increased by 12% (P<0.05). Changes in plasma TG were positively correlated with reductions in large (r=0.615, P<0.01) and medium VLDL particles (r=0.432, P<0.05) and negatively correlated with LDL diameter (r=-0.489, P<0.01). Changes in trunk fat were positively correlated with medium VLDL (r=0.474, P<0.0) and small LDL (r=0.405, P<0.05) and negatively correlated with large HDL (r=-0.556, P<0.01). We conclude that weight loss induced by CR favorably alters the secretion and processing of plasma lipoproteins, rendering VLDL, LDL, and HDL particles associated with decreased risk for atherosclerosis and coronary heart disease.

OBJECTIVE

Gluteo-femoral, in contrast to abdominal, fat accumulation appears protective against diabetes and cardiovascular disease. Our objective was to test the hypothesis that this reflects differences in the ability of the two depots to sequester fatty acids, with gluteo-femoral fat acting as a longer-term "sink."

METHODS

A total of 12 healthy volunteers were studied after an overnight fast and after ingestion of a mixed meal. Blood samples were taken from veins draining subcutaneous femoral and abdominal fat and compared with arterialized blood samples. Stable isotope-labeled fatty acids were used to trace specific lipid fractions. In 36 subjects, adipose tissue blood flow in the two depots was monitored with (133)Xe.

RESULTS

Blood flow increased in response to the meal in both depots, and these responses were correlated (r(s) = 0.44, P < 0.01). Nonesterified fatty acid (NEFA) release was suppressed after the meal in both depots; it was lower in femoral fat than in abdominal fat (P < 0.01). Plasma triacylglycerol (TG) extraction by femoral fat was also lower than that by abdominal fat (P = 0.05). Isotopic tracers showed that the difference was in chylomicron-TG extraction. VLDL-TG extraction and direct NEFA uptake were similar in the two depots.

CONCLUSIONS

Femoral fat shows lower metabolic fluxes than subcutaneous abdominal fat, but differs in its relative preference for extracting fatty acids directly from the plasma NEFA and VLDL-TG pools compared with chylomicron-TG.

A biochemical, histologic and morphometric evaluation of spontaneous, diet-induced (thoracic aorta) and injury-induced (iliac-femoral) atherosclerotic lesions was performed in rabbits maintained on varying levels of dietary cholesterol. Rabbits were meal-fed a 3% peanut oil, 3% coconut oil diet containing 0%, 0.1%, 0.25%, 0.5%, 1.0%, 1.5% or 2.0% cholesterol for 9 weeks. Plasma total cholesterol exposure (area under cholesterol-time curve (TC-AUC)) increased diet-dependently over the course of the study. VLDL and LDL cholesterol (VLDL-C, LDL-C) comprised 41% and 55%, respectively, of the plasma total cholesterol at cholesterol levels>> 700 mg/dl (TC-AUC>> 31,868 mg day/dl) and both VLDL-C and LDL-C were linearly related to TC-AUC (r = 0.98). Plasma TC-AUC was linearly related to thoracic aortic cholesteryl ester (CE) content (r = 0.74) and thoracic aortic lesion coverage (r = 0.66). In the injury-induced iliac-femoral lesion, plasma TC-AUC was linearly related to both iliac-femoral CE content (r = 0.80) and macrophage/lesion ratio (r = 0.64). At plasma cholesterol levels greater than 700 mg/dl, CE content of the iliac-femoral lesion ranged from 35 to 69 micrograms/mg dry defatted tissue,>> 75% of the lesions were fibrofoamy in nature and macrophage/lesion area ratio was 0.46 to 0.55 while lesion area remained constant. VLDL-C and LDL-C were highly correlated with the CE content of both thoracic and iliac-femoral lesions, thoracic aortic lesion coverage and macrophage/lesion area ratio (r = 0.86-0.99). We conclude that the composition, extent and type of atherosclerotic lesion induced in rabbits is dependent upon the overall plasma cholesterol exposure, VLDL and LDL cholesterol content and whether lesions are induced by diet alone or both diet and chronic endothelial injury. In addition, various stages of atherosclerotic lesion formation can be replicated in the rabbit by titrating the animal's overall plasma cholesterol exposure.

Appearance, pharmacokinetics and distribution of astaxanthin all-E-, 9Z- and 13Z-geometrical and (3R,3'R)-, (3R,3'S)- and (3S,3'S)-optical isomers in plasma fractions were studied in three middle-aged male volunteers (41-50 years) after ingestion of a single meal containing first a 10-mg dose equivalent of astaxanthin from astaxanthin diesters, followed by a dose of 100 mg astaxanthin equivalents after 4 weeks. Direct resolution of geometrical isomers and optical isomers of astaxanthin dicamphanates by HPLC after saponification showed that the astaxanthin consisted of 95.2% all-E-, 1.2% 9Z- and 3.6% 13Z-astaxanthin, of (3R,3'R)-, (3R,3'S; meso)- and (3S,3'S)-astaxanthin in a 31:49:20 ratio. The plasma astaxanthin concentration-time curves were measured during 76 h. Astaxanthin esters were not detected in plasma. Maximum levels of astaxanthin (C(max)=0.28+/-0.1 mg/l) were reached 11.5 h after administration and the plasma astaxanthin elimination half-life was 52+/-40 h. The C(max) at the low dose was 0.08 mg/l and showed that, the dose response was non-linear. The (3R,3'R)-astaxanthin optical isomer accumulated selectively in plasma compared to the (3R,3'S)- and (3S,3'S)-isomers, and comprised 54% of total astaxanthin in the blood and only 31% of total astaxanthin in the administered dose. The astaxanthin Z-isomers were absorbed selectively into plasma and comprised approximately 32% of total astaxanthin 6-7.5 h postprandially. The proportion of all-E-astaxanthin was significantly higher in the very low density lipoproteins and chylomicrons (VLDL/CM) plasma lipoprotein fraction than in the high density lipoproteins (HDL) and low denisty lipoproteins (LDL) fractions (P<0.05). The results indicate that a selective process increase the relative proportion of astaxanthin Z-isomers compared to the all-E-astaxanthin before uptake in blood and that the astaxanthin esters are hydrolyzed selectively during absorption.

Lecithin cholesterol acyl transferase (LCAT) deficiency is associated with low high-density lipoprotein (HDL) and the presence of an abnormal lipoprotein called lipoprotein X (Lp-X) that contributes to end-stage renal disease. We examined the possibility of using LCAT an as enzyme replacement therapy agent by testing the infusion of human recombinant (r)LCAT into several mouse models of LCAT deficiency. Infusion of plasma from human LCAT transgenic mice into LCAT-knockout (KO) mice rapidly increased HDL-cholesterol (C) and lowered cholesterol in fractions containing very-low-density lipoprotein (VLDL) and Lp-X. rLCAT was produced in a stably transfected human embryonic kidney 293f cell line and purified to homogeneity, with a specific activity of 1850 nmol/mg/h. Infusion of rLCAT intravenously, subcutaneously, or intramuscularly into human apoA-I transgenic mice showed a nearly identical effect in increasing HDL-C approximately 2-fold. When rLCAT was intravenously injected into LCAT-KO mice, it showed a similar effect as plasma from human LCAT transgenic mice in correcting the abnormal lipoprotein profile, but it had a considerably shorter half-life of approximately 1.23 ± 0.63 versus 8.29 ± 1.82 h for the plasma infusion. rLCAT intravenously injected in LCAT-KO mice crossed with human apolipoprotein (apo)A-I transgenic mice had a half-life of 7.39 ± 2.1 h and increased HDL-C more than 8-fold. rLCAT treatment of LCAT-KO mice was found to increase cholesterol efflux to HDL isolated from mice when added to cells transfected with either ATP-binding cassette (ABC) transporter A1 or ABCG1. In summary, rLCAT treatment rapidly restored the normal lipoprotein phenotype in LCAT-KO mice and increased cholesterol efflux, suggesting the possibility of using rLCAT as an enzyme replacement therapy agent for LCAT deficiency.

OBJECTIVE

Common carotid artery intima-media thickness (CIMT) is a non-invasively assessed marker of subclinical atherosclerosis. Our aim in this study was to investigate CIMT in women with gestational diabetes mellitus (GDM).

METHODS

Thirty women with GDM and 40 unaffected women (as a control group) were included in the study. Blood samples were drawn from each woman in the morning after they had fasted for at least 8 h, and levels of fasting glucose, insulin, homocysteine, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol were measured, along with the CIMT in the two groups.

RESULTS

The mean triglyceride (P = 0.016) and VLDL cholesterol (P = 0.011) levels in the GDM group were significantly higher than those in the unaffected women. There were no significant differences between the groups with respect to plasma levels of total cholesterol, HDL cholesterol, LDL cholesterol and insulin. The mean homocysteine (P = 0.027) and fasting glucose (P = 0.019) levels in women with GDM were significantly higher than those in the control group. Patients with GDM had significantly higher CIMT than did the unaffected women (0.582 +/- 0.066 mm vs. 0.543 +/- 0.049 mm, P = 0.006). CIMT correlated positively with maternal age (r = 0.316, P = 0.008), body mass index (BMI) at the time of a 50-g oral glucose load test (r = 0.414, P = 0.001) and homocysteine levels (r = 0.332, P = 0.008), and fasting glucose (r = 0.265, P = 0.031) and 1-h glucose value (r = 0.410, P = 0.001) at the time of the oral glucose tolerance test. There was a positive correlation between the presence of GDM and CIMT (r = 0.372, P = 0.001). However, stepwise multiple regression analysis showed that GDM/no GDM (95% CI +0.012 to +0.076, P = 0.008) and BMI at the time of the 50-g test (95% CI +0.001 to +0.009, P = 0.011) were independent parameters related to CIMT.

CONCLUSIONS

Women with GDM have increased CIMT compared with unaffected women.

BACKGROUND

Psoriasis is a common chronic and recurrent inflammatory skin disease that can occur due to abnormalities in essential fatty acid metabolism, lymphokine secretion, free radical generation, lipid peroxidation and eicosanoid metabolism, and has been associated with increased frequency of cardiovascular events. The current study was designed to evaluate plasma lipids, susceptibility of LDL to oxidation and oxidant-antioxidant status and their relationships in patients with psoriasis.

METHODS

The study group included 35 patients with psoriasis (18 females and 17 males), and 35 sex- and age-matched healthy volunteers (16 females and 19 males). From blood samples, their lipids, lipoproteins, acute phase reactants, lipid peroxidation products [lipid hydroperoxide (LHP) and malondialdehyde (MDA)], antioxidant enzymes [glutathione peroxidase (GSH-Px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT)], total antioxidant status (TAS) and autoantibodies against oxidized low-density lipoprotein (AuAb-oxLDL) levels were determined. Moreover, the susceptibility of copper-induced in vitro oxidation of LDL was examined.

RESULTS

The mean levels of atherogenic lipids (total cholesterol [TC], triacylglycerol [TG] and LDL cholesterol [LDL-C]), acute-phase reactants (CRP, ESR, PMNLs, ceruloplasmin and fibrinogen) and lipid peroxidation products, AuAb-oxLDL levels in patients with psoriasis were found to be significantly higher than those of healthy subjects. On the other hand, TAS and antioxidant enzyme activities (CAT, SOD and GSH-Px in erythrocyte and SOD in plasma) were significantly lower when compared to healthy subjects. The lag times [t(lag)], a measure of resistance to oxidation of LDL, were also lower. The levels of AuAb-oxLDL in patients were correlated with TC, LDL-C, plasma LHP, erythrocyte MDA, oxidized LDL-MDA (oxLDL-MDA), fibrinogen, CRP, PMNL levels and plasma SOD activities (r = 0.69, P < 0.01; r = 0.64, P < 0.01; r = 0.38, P < 0.05; r = 0.65, P < 0.01; r = 0.34, P < 0.05; r = 0.34, P < 0.05; r = 0.53, P < 0.01, r = 0.34, P < 0.05; r = -0.67, P < 0.01, respectively). On the other hand, t(lag) was correlated negatively with the levels of VLDL-TG, VLDL-TC and LDL-TG but positively correlated with the levels of TAS in psoriatics (r = -0.49, P < 0.01; r = -0.49, P < 0.01, r = -0.65, P < 0.05; r = 0.37, P < 0.05).

CONCLUSIONS

It was concluded that the psoriatic patients could be considered as a group with an increased atherosclerotic risk because of increased oxidant stress, decreased antioxidant capacity and susceptibility in lipid profile and lipoprotein content to atherogenicity.

The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a primed-constant infusion of (5,5,5-(2)H(3)) leucine in the fed state (hourly feeding) in 19 subjects after consumption of an average American diet (36% fat). Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS gels, and isotope enrichment was assessed by gas chromatography/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and LDL apoB-100 were 17+/-10, 273+/-167, and 3325+/-1146 mg, respectively. There was a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than for TRL apoB-48 (6.73+/-3.48 versus 5.02+/-2.07 pools/d, respectively, P=0.06). The mean FCRs for IDL and LDL apoB-100 were 10.07+/-7.28 and 0.27+/-0.08 pools/d, respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB-100 (1. 3+/-0.90 versus 20.06+/-6.53 mg. kg(-1). d(-1), P<0.0001). TRL apoB-48 PS was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=-0.1810, P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and FCR (r=-0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004). LDL apoB-100 PS was correlated with FCR (r=-0.549, P=0.015). These data indicate that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state, (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4) LDL apoB-100 PS is correlated with LDL FCR.