OBJECTIVE

Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study's aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.

METHODS

Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/lipoprotein evaluation was performed by vertical auto profile methodology.

METHODS

Academic medical center.

METHODS

107 nondiabetic, overweight/obese adults.

RESULTS

Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDLr = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.

CONCLUSIONS

Pro-atherogenic lipoprotein abnormalities in obstructive sleep apnea (OSA) are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased cardiovascular disease risk.

Blood samples were obtained from 12 Iranian fat-tailed sheep during 7 weeks pre-partum, at parturition and 7 weeks post-partum. The lipids measured were cholesterol, triglyceride, total lipid, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and very low-density lipoprotein (VLDL)-cholesterol. The concentrations of cholesterol, triglyceride, HDL-cholesterol and VLDL-cholesterol during the 7 weeks pre-partum, at parturition and the 7 weeks post-partum were significantly different (P < 0.05). One week before parturition, the concentrations of cholesterol, triglyceride, HDL-cholesterol and VLDL-cholesterol were higher (P < 0.05) than at other periods. The lowest concentrations of these parameters were observed 2-3 weeks after parturition. In this study, significant positive correlations were observed between the time of sampling (pre-partum, parturition and post-partum) and serum cholesterol (r = 0.22; P < 0.01) and HDL-cholesterol (r = 0.25; P < 0.01).

Some cardiovascular complications in patients with chronic kidney disease and end-stage renal disease may be caused by structurally and functionally modified lipoproteins. Redox status (advanced oxidation protein products [AOPPs]), prooxidant-antioxidant balance, total protein sulfhydryl (SH-groups), and paraoxonase 1 (PON1) activity were assessed in 77 renal patients and 20 controls. Lipoproteins were isolated using ultracentrifugation. PON1, PON3, and pentraxin-3 concentration were determined by enzyme-linked immunosorbent assay (ELISA). Dyslipidemia-Oxy-Inflammation (DOI) score was calculated as a sum of dyslipidemia, oxidative stress, and inflammation scores. The dyslipidemia score ( P < .001), oxy score ( P < .01), inflammation score (P < .001), and the DOI score ( P < .001) were higher in patient groups compared with controls. The very-low-density lipoprotein (VLDL) fraction contained the highest amount of AOPP ( P < .001) compared with other lipoprotein fractions in all groups. The low-density lipoprotein (LDL) fraction contained elevated AOPP in all groups compared with the high-density lipoprotein (HDL) fraction ( P < .001). Significant positive correlation was observed between AOPP in LDL fraction and DOI score (ρ = 0.510, P < .01). Dyslipidemia, oxidative stress, and inflammation play an interactive role in renal disease and are mutually associated with redox status in VLDL, LDL, and HDL lipoproteins in plasma of renal patients.

OBJECTIVE

The effects of lean fish on plasma lipoproteins, postheparin plasma lipolytic activities and sex hormones were examined in 11 normolipidemic male subjects.

METHODS

This study was a randomized crossover trial of two isoenergetic prudent-type diets, lean fish diet and beef, pork, veal, eggs and milk (nonfish) diet. Experimental diets provided approximately 11800 kJ--18% as proteins, 50% as carbohydrates, 32% as lipids [ratio of polyunsaturated to saturated fatty acids (P:S) of 1:1 compared with 0.5:1 in preexperimental diet], and 260 mg cholesterol/day.

RESULTS

Compared with the nonfish diet, the lean fish diet induced higher plasma total and LDL apolipoprotein (apo) B and apo B:apo A-1 ratio, indicating that the substitution of lean fish for beef, veal, pork, eggs and milk provides little benefits with regard to plasma apo B concentrations in a low-fat high P:S diet. Moreover, triglycerides:apo B and cholesterol:apo B ratios of VLDL were lower following the lean fish diet than the nonfish diet, suggesting the presence of smaller very low-density lipoprotein (VLDL) particles following the consumption of lean fish. Higher plasma concentrations of sex hormone-binding globulin (SHBG), HDL2 cholesterol and HDL2:HDL3 cholesterol ratio were found with the lean fish diet compared with the nonfish diet. Negative correlations between plasma postheparin lipoprotein lipase (LPL) activity and VLDL triglycerides (n = 11, r = -0.53, p = 0.02), and between plasma postheparin LPL activity and VLDL triglycerides:apo B ratio (n = 11, r = -0.64, p = 0.02) were also observed following the lean fish diet.

CONCLUSIONS

These results suggest that the effects of substituting lean fish for beef, veal, pork, eggs and milk on plasma lipoproteins may be partly associated with variations in plasma sex hormone status and plasma LPL activity in normolipidemic men.

Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy.

OBJECTIVE

Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency.

METHODS

VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated.

RESULTS

HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased.

CONCLUSIONS

The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and dysfunction can directly affect hypertriglyceridaemia development.

UNASSIGNED

What is the central question of this study? Does short-duration, high-intensity exercise training that combines functional aerobic and resistance exercises into training sessions lasting 8-20 min benefit individuals with type 2 diabetes? What is the main finding and its importance? Functional high-intensity training improves insulin sensitivity and reduces cardiometabolic risk in individuals with type 2 diabetes. This type of exercise training may be an effective exercise mode for managing type 2 diabetes. The increase in insulin sensitivity addresses a key defect in type 2 diabetes.

UNASSIGNED

Functional high-intensity training (F-HIT) is a novel fitness paradigm that integrates simultaneous aerobic and resistance training in sets of constantly varied movements, based on real-world situational exercises, performed at high-intensity in workouts that range from ∼8 to 20 min per session. We hypothesized that F-HIT would be an effective exercise mode for reducing insulin resistance in type 2 diabetes (T2D). We recruited 13 overweight/obese adults (5 males, 8 females; 53 ± 7 years; BMI 34.5 ± 3.6 kg m-2 , means ± SD) with T2D to participate in a 6-week (3 days week-1 ) supervised F-HIT programme. An oral glucose tolerance test was used to derive measures of insulin sensitivity. F-HIT significantly reduced fat mass (43.8 ± 83.8 vs. 41.6 ± 7.9 kg; P < 0.01), diastolic blood pressure (80.2 ± 7.1 vs. 74.5 ± 5.8; P < 0.01), blood lipids (triglyceride and VLDL, both P < 0.05) and metabolic syndrome z-score (6.4 ± 4.5 vs. -0.2 ± 5.2 AU; P < 0.001), and increased basal fat oxidation (0.08 ± 0.03 vs. 0.10 ± 0.04 g min-1 ; P = 0.05), and high molecular mass adiponectin (214.4 ± 88.9 vs. 288.8 ± 127.4 ng mL-1 ; P < 0.01). Importantly, F-HIT also increased insulin sensitivity (0.037 ± 0.010 vs. 0.042 ± 0.010 AU; P < 0.05). Increases in high molecular mass adiponectin and basal fat oxidation correlated with the change in insulin sensitivity (ρ, 0.75, P < 0.05 and ρ, 0.81, P < 0.01, respectively). Compliance with the training programme was >95% and no injuries or adverse events were reported. These data suggest that F-HIT may be an effective exercise mode for managing T2D. The increase in insulin sensitivity addresses a key defect in T2D and is consistent with improvements observed after more traditional aerobic exercise programmes in overweight/obese adults with T2D.

BACKGROUND

Multiple occasions of device-measured physical activity have not been previously examined in relation to metabolic traits. We described associations of total activity, moderate-to-vigorous physical activity (MVPA), and sedentary time from three accelerometry measures taken across adolescence with detailed traits related to systemic metabolism.

RESULTS

There were 1,826 male and female participants recruited at birth in 1991-1992 via mothers into the Avon Longitudinal Study of Parents and Children offspring cohort who attended clinics in 2003-2005, 2005-2006, and 2006-2008 who were included in ≥1 analysis. Waist-worn uniaxial accelerometers measured total activity (counts/min), MVPA (min/d), and sedentary time (min/d) over ≥3 d at mean age 12y, 14y, and 15y. Current activity (at age 15y), mean activity across occasions, interaction by previous activity, and change in activity were examined in relation to systolic and diastolic blood pressure, insulin, C-reactive protein, and 230 traits from targeted metabolomics (nuclear magnetic resonance spectroscopy), including lipoprotein cholesterol and triglycerides, amino and fatty acids, glycoprotein acetyls, and others, at age 15y. Mean current total activity was 477.5 counts/min (SD = 164.0) while mean MVPA and sedentary time durations were 23.6 min/d (SD = 17.9) and 522.1 min/d (SD = 66.0), respectively. Mean body mass index at age 15y was 21.4 kg/m2 (SD = 3.5). Correlations between first and last activity measurement occasions were low (e.g., r = 0.40 for counts/min). Current activity was most strongly associated with cholesterol and triglycerides in high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles (e.g., -0.002 mmol/l or -0.18 SD units; 95% CI -0.24--0.11 for triglycerides in chylomicrons and extremely large very low-density lipoprotein [XL VLDL]) and with glycoprotein acetyls (-0.02 mmol/l or -0.16 SD units; 95% CI -0.22--0.10), among others. Associations were similar for mean activity across 3 occasions. Attenuations were modest with adjustment for fat mass index based on dual-energy X-ray absorptiometry (DXA). In mutually adjusted models, higher MVPA and sedentary time were oppositely associated with cholesterol and triglycerides in VLDL and HDL particles (MVPA more strongly with glycoprotein acetyls and sedentary time more strongly with amino acids). Associations appeared less consistent for sedentary time than for MVPA based on longer-term measures and were weak for change in all activity types from age 12y-15y. Evidence was also weak for interaction between activity types at age 15y and previous activity measures in relation to most traits (minimum P = 0.003; median P = 0.26 for counts/min) with interaction coefficients mostly positive. Study limitations include modest sample sizes and relatively short durations of accelerometry measurement on each occasion (3-7 d) and of time lengths between first and last accelerometry occasions (<4 years), which can obscure patterns from chance variation and limit description of activity trajectories. Activity was also recorded using uniaxial accelerometers which predated more sensitive triaxial devices.

CONCLUSIONS

Our results support associations of physical activity with metabolic traits that are small in magnitude and more robust for higher MVPA than lower sedentary time. Activity fluctuates over time, but associations of current activity with most metabolic traits do not differ by previous activity. This suggests that the metabolic effects of physical activity, if causal, depend on most recent engagement.

Familial hypercholesterolemia (FH) is a common autosomal disorder associated with hypercholesterolemia which usually results from a mutation in the coding region of the low density lipoprotein (LDL) receptor (R) activity. Only 20% of untreated heterozygote (h) FH men reach 70 years of age. Therefore, the diagnosis of hFH is a better predictor of coronary heart disease than risk-based algorithms. Fasting and postprandial hypertriglyceridemia are also considered as risk factors for atherosclerosis. The plasma triglycerides (TG)s are formed from two major sources; intestinally-derived chylomicrons and hepatically-derived very low density lipoproteins (VLDL). Potentially, atherogenic remnants of TG-rich lipoproteins accumulate in the postprandial state. In addition, TG-rich lipoproteins may promote the formation of atherogenic small dense LDL. In FH subjects, lipoprotein metabolism seems to be impaired and may contribute to premature atherosclerosis. This was documented in many studies in which mice lacking LDLR present hypercholesterolemia, increased plasma TG-rich lipoprotein remnants and develop premature spontaneous atherosclerosis. In this review, we focus on the current knowledge regarding TG metabolism on a selected clinically condition such as FH. Variation in clinical characteristics has been described between studies which may occur due to dissimilarity in the molecular defect of FH. Additionally, the relationship between TG levels in FH subjects and the development of atherosclerosis, as well as the appropriate treatment for these patients is analysed.

Plasma cholesteryl ester transfer protein (CETP) promotes the cholesterol enrichment of apoB-containing lipoproteins (VLDL and LDL) at the expense of HDL. Recent studies demonstrated that apoC1 is a potent CETP inhibitor in plasma of healthy, normolipidemic subjects. Our goal was to establish whether the modulation of CETP activity by apoC1 is influenced by dyslipidemia in patients with documented coronary artery disease (CAD). In the total CAD population studied (n = 240), apoC1 levels correlated negatively with CETP activity, independently of apoE-epsilon, CETP-Taq1B, and apoC1-Hpa1 genotypes. In multivariate analysis, the negative relationship was observed only in normolipidemic patients, not in those with hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia. In the normolipidemic subjects, apoC1 levels were positively associated with higher HDL- to LDL-cholesterol ratio (r = 0.359, P < 0.001). It is concluded that apoC1 as a CETP inhibitor no longer operates on cholesterol redistribution in high-risk patients with dyslipidemia, probably due to increasing amounts of VLDL-bound apoC1, which is inactive as a CETP inhibitor. Patients with dyslipidemia could experience major benefits from treatment with pharmacological CETP inhibitors, which might compensate for blunted endogenous inhibition.

The purpose of this study was to examine the effects of insulin resistance on the lipoprotein subpopulation distribution of very-low-density, low-density, and high-density lipoproteins (VLDL, LDL, and HDL) in lean and morbidly obese nondiabetic women. Lean women (body mass index [BMI], 20 to 27 kg/m2) stratified by BMI were divided into insulin-sensitive (SL, n = 12) and insulin-resistant (RL, n = 8) groups according to Bergman's minimal model, SI. A group of obese women (BMI, 30 to 53 kg/m2), also stratified by BMI, were divided into insulin-sensitive (SO, n = 10) and insulin-resistant (RO, n = 11) groups in a similar fashion. Resistant groups were similar to sensitive groups (SL v RL and SO vRO) in age, weight, percent body fat, and waist circumference, ie, total and regional adiposity. VLDL, LDL, and HDL subpopulation distributions were determined in fasting plasma samples by nuclear magnetic resonance (NMR) spectroscopy. The average particle sizes of all 3 classes of lipoproteins were similar for the SL and RL groups. In contrast, RO subjects had larger VLDL, smaller LDL, and smaller HDL, than SO subjects (P < .05). Lower concentrations of large LDL and large HDL were found in RO compared with SO subjects (P < .05). In obese women, but not in lean women, VLDL size was associated with plasma insulin (r = .60, P < .005), while LDL size and HDL size were negatively correlated with plasma insulin (r = -.39, P < .05 and r = -.38, P < .05) and positively correlated with SI (r = .54, P < .01 and r = .42, P < .05). These results suggest that in obese women, insulin resistance may be involved in the formation of lipoprotein subpopulation distributions that are associated with vascular disease.

The in vitro micellar cholesterol displacement assay has been used to identify peptides that may potentially reduce cholesterol in vivo. Two of these peptides, LPYPR and WGAPSL, derived from soybean protein (SP) that have been reported to displace cholesterol from micelles were tested by feeding them as a part of a hypercholesterolemic diet to mice for 3 weeks. Except reduction of very low-density lipoprotein cholesterol (VLDL-C) and triglyceride contents, the peptide-containing diets increased plasma cholesterol content with the increasing dose of the peptides. Mice fed diets supplemented with the peptides also had lower fecal bile acid excretion. Negative correlations between fecal bile acid excretion and plasma total cholesterol content (r = -0.876, P = 0.062) and non-HDL-C content (r = -0.831, P = 0.084) were observed. The mRNA levels of the genes for cholesterol and bile acid metabolism, CYP51, LDLR, CYP7A1, and LPL, were up-regulated in mice fed diets supplemented with peptides except the group fed the low dose of WGAPSL. The results suggested that higher plasma total cholesterol content possibly due to lower fecal steroid excretion as well as lower VLDL-C and triglyceride contents might due to the up-regulated expression levels of the genes CYP51, LDLR, and LPL.

OBJECTIVE

A convenient method based on anion-exchange HPLC was recently developed to determine cholesterol levels of lipoproteins (HDL, LDL, IDL, VLDL, and chylomicron). The present study was performed to compare this HPLC method to homogenous assay in regard to measurement accuracy of HDL and LDL cholesterol.

METHODS

Serum samples (n=105), including three samples from cholestasis patients, were measured by homogenous assay with Cholestest-LDL and CholestestN-HDL (Daiichi Chemicals, Tokyo) and by HPLC as reported previously (J Lipid Res 2003; 44: 1404-12).

RESULTS

The homogenous assay for HDL cholesterol correlated strongly with the HPLC method for HDL cholesterol (r=0.976). Two samples from cholestasis patients could not be measured by homogenous assay but were measured by HPLC. The homogenous assay for LDL cholesterol correlated modestly with the HPLC method for LDL cholesterol (r=0.823). Three outlier samples, from cholestasis patients with serum cholesterol levels >17 mmol/L, were observed in this correlation analysis. Homogenous assay data showed that these LDL cholesterol levels were 15.2-34.7 mmol/L. However, HPLC data showed that these LDL cholesterol levels were 3.6-8.2 mmol/L, and that the major lipoprotein fractions were VLDL and IDL. The difference in LDL cholesterol levels (homogenous assay data minus HPLC data) was positively correlated with VLDL cholesterol levels.

CONCLUSIONS

When measuring samples from cholestasis patients, homogenous assay may give inaccurate results. In contrast, the HPLC method is likely to be capable of accurately measuring HDL and LDL cholesterol levels without the involving VLDL.

OBJECTIVE

To investigate the mechanism of lipid-lowering effect of the Astragalus mongholicus and Angelica sinensis compound (A&A) on nephrotic hyperlipidemia in rats.

METHODS

Rats with nephrotic syndrome from accelerated nephrotoxic serum nephritis were used. They were divided into two groups: A&A treatment group and nephrotic control group. Normal rats were used as a normal control group. Serum lipids, serum lipoprotein lipase (LPL) and lecithin-cholesterol acyltransferase (LCAT) were assayed biochemically and enzymatically. mRNAs of hepatic hydroxy-methyl glutaryl-CoA reductase (HMG-CoA-R) and low-density lipoprotein receptor (LDL-R) were assessed by Northern blot.

RESULTS

In nephrotic control group hyperlipidemia was found. The activities of serum LPL and LCAT were low. Hepatic HMG-CoA-R mRNA increased temporarily at the early stage while LDL-R mRNA decreased gradually. In A&A treatment group, serum total cholesterol (TC), triglyceride (TG), low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL) were significantly lower than those in nephrotic control group. There was no change in the amount of hepatic HMG-CoA-R mRNA, but hepatic LDL-R mRNA and activities of serum LPL and LCAT increased significantly.

CONCLUSIONS

A&A alleviates hyperlipidemia considerably in nephrotic rats. A&A improves disorders of lipid metabolism perhaps through up-regulating the expression of hepatic LDL-R gene and through increasing the activities of serum LPL and LCAT.

OBJECTIVE

The risk of cardiovascular disease in type 2 diabetes is greater than is accounted for by conventional risk factors. We investigated whether energy restriction or modest fat loss improved the lipid profile in obese subjects with and without type 2 diabetes. The relationship of site of adipose tissue loss to lipid changes was also examined.

METHODS

Lipid levels were measured in 18 subjects with normal glucose tolerance (NGT) (n = 9, BMI = 31.5 +/- 0.8 [SEM] kg/m2) or type 2 diabetes (n = 9, BMI = 31.8 +/- 0.7) before and on the 4th (d4) and 28th (d28) days of a hypocaloric formula diet. Body composition was assessed with dual energy X-ray absorptiometry on d0 and d28.

RESULTS

Mean daily energy intake during the diet was 1,100 +/- 60 kcal (33% protein, 38% carbohydrate, and 29% fat). Mean weight loss was 6.2 +/- 0.4 kg. Initial lipid profiles were similar in subjects with or without diabetes, and diabetes did not affect the responses. Dietary intervention resulted in early (d4) and late (d28) changes. Energy restriction (d4) reduced VLDL cholesterol and total triglyceride (TG) concentrations and increased LDL particle size. LDL TG, and LDL apolipoprotein B (apoB) concentrations. Reduction in central abdominal fat (but not other body fat) was correlated with a less atherogenic lipid profile: delta abdominal fat versus delta LDL free cholesterol, r = 0.65, P = 0.006 and versus delta apoB, r = 0.64, P = 0.008.

CONCLUSIONS

Even in obese subjects with an average lipid profile, modest weight loss reduces atherogenicity, independently of type 2 diabetes, and abdominal fat loss is specifically related to such improvements.

OBJECTIVE

Patients with familial combined hyperlipidemia (FCH) have an increased cardiovascular mortality despite only moderate elevations of LDL-cholesterol. Since endothelial NO release is intimately involved in the anti-atherosclerotic effects of the endothelium, we studied the effect of short-term lipid-lowering therapy on NO-mediated vasodilatation in patients with FCH. In view of only moderate LDL elevations, we evaluated whether alterations in other lipid fractions upon therapy correlated to changes in NO-mediated vasodilatation.

METHODS

NO activity was assessed by serotonin-induced, nitric oxide-mediated increase in forearm blood flow (FBF). Measurements were performed 2 weeks off and 4 weeks on lipid-lowering therapy in 12 FCH patients using forearm venous occlusion plethysmography. Control experiments were performed in 12 healthy subjects.

RESULTS

Serotonin-induced vasodilatation was impaired in FCH patients (FBF (unit ml/100 ml forearm tissue/min) from 3.0 (0.3) to 4.8 (0.4)) compared to controls (FBF from 2.9 (0.3) to 6.5 (0.6); p < 0.05 vs. FCH). FBF response to serotonin improved significantly upon lipid-lowering therapy (from 3.0 (0.3) to 5.7 (0.5); p < 0.05 treated vs. untreated). The level of improvement in endothelial function was significantly correlated to the absolute reduction of intermediate density lipoproteins upon lipid-lowering therapy (r = -0.64; p < 0.05), whereas it did not correlate to changes in VLDL- or LDL-cholesterol, nor to Lp(a).

CONCLUSIONS

Patients with familial combined hyperlipidemia have impaired NO-mediated vasodilatation, that responds rapidly to lipid lowering medication, and may be related to changes in intermediate density lipoproteins.

The hypothesis that the apoprotein composition of nascent very-low-density lipoprotein (VLDL) secreted by the hepatocyte is determined by the relative rates of apoprotein synthesis and their affinities of binding to VLDL was tested using chick hepatocytes in monolayer culture. Chick cells were chosen for the study of lipoprotein assembly since estradiol treatment can be used to alter the composition of the apoprotein mixture synthesized by these cells. The secretion of apoprotein (apo) B by estradiol-treated hepatocytes was elevated 4.2-fold above the basal level measured in control cells. Furthermore, estradiol-treated cells secreted apo-II, a major VLDL apoprotein not synthesized prior to estradiol treatment, at a level equivalent to that of apo-B. However, no difference in the secretion of apo-A-I and other newly identified nascent VLDL apoproteins was detected. These changes in relative rates of apoprotein synthesis altered the composition of nascent VLDL secreted by control versus estradiol-induced cells from: apo-B, 22 to 40%; apo-II, 0 to 32%; apo-37 kDa, 14 to 6%; apo-A-I, 31 to 12%; apo-17 kDa, 10 to 4%; apo-9 kDa, 15 to less than 10%; and apo-6 kDa, 8 to less than 2%. To investigate the basis for the preferential incorporation of apo-B and apo-II into nascent VLDL, the relative affinities of the apoproteins for VLDL were compared by measuring their capacities to transfer from VLDL into other lipoprotein or nonlipoprotein density classes. Culture medium containing [3H]leucine-labeled VLDL was incubated with plasma deficient in lipoproteins of rho less than 1.006 g/ml. Within 30 min of incubation at 37 degrees C, 3H-labeled apo-A-I and apo-9 kDa exchanged between VLDL and high-density lipoprotein, whereas apo-37 kDa exchanged between VLDL and the rho greater than 1.21 g/ml fraction. Neither apo-B nor apo-II underwent transfer from nascent VLDL. These results suggest that the relative rates of input of apoproteins into the secretory pathway and their affinities of binding to the nascent VLDL particle determine their extent of incorporation into, and, thus, the apoprotein composition of secreted VLDL.

BACKGROUND

Several epidemiological studies have shown that postprandial hyperglycemia is associated with an increased risk of cardiovascular disease (CVD). The present study was conducted in order to compare the effects of acarbose and glimepiride treatment on serum lipoprotein profiles in patients with type 2 diabetes.

METHODS

A total of 37 patients with newly diagnosed type 2 diabetes were studied. The patients were assigned randomly to treatment for 12 weeks with either acarbose (n=13, 100 mg x 3/day, group A), glimepiride (n=13, 2 mg/day, group G) or diet only (n=11, group D). Lipid and lipoprotein profiles before and after each treatment were evaluated.

RESULTS

A significant reduction in the net electronegative charge of low-density lipoprotein (emLDL) was observed in group A (-1.8, P<0.01), whereas no significant change in emLDL was observed in groups G and D. In group A, small VLDL and very small LDL levels were also decreased significantly (P<0.05). The change in emLDL levels correlated significantly with changes in very small LDL (r=0.751, P<0.01) and oxidized LDL levels (r=0.623, P<0.05).

CONCLUSIONS

These results suggest that measurement of serum emLDL may be a sensitive and clinically useful marker for determining qualitative lipoprotein abnormalities in diabetes, and that acarbose treatment lowers CVD risk by decreasing production of emLDL.

We evaluated changes in low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase gene expression in women with metabolic syndrome and elevated plasma LDL cholesterol (LDL-C). We hypothesized that expression of these 2 genes would be modulated by our dietary intervention. Twenty-five women were instructed to follow a Mediterranean-style low-glycemic-load diet for 12 weeks. Quantitative real-time polymerase chain reaction was used to measure messenger RNA (mRNA) abundance of the LDL receptor and HMG-CoA reductase in mononuclear cells, which were used as a proxy of liver expression of these 2 genes. All women experienced favorable impacts on metabolic syndrome variables, with decreases in waist circumference (P < .001), plasma triglycerides (P < .05), and systolic blood pressure (P < .05) compared with baseline. Furthermore, participants had reductions in LDL-C (P < .01), plasma insulin (P < .001), and homeostatic model assessment score for insulin resistance (P < .001) over time. In addition, significant decreases were found in plasma tumor necrosis factor α (P < .01), which might have contributed to the improvements observed in insulin resistance. Although no changes in LDL-receptor mRNA levels were observed, HMG-CoA-reductase gene expression was reduced (P < .001) after 12 weeks. The reductions in plasma insulin correlated with changes in HMG-CoA-reductase mRNA levels (r = 0.45, P < .01). In conclusion, the observed reductions in plasma insulin may have affected the expression of a key regulatory gene of cholesterol synthesis, HMG-CoA reductase. The decreased HMG-CoA-reductase expression may be related to lower secretion of very low density lipoprotein (VLDL)-cholesterol, which, in turn, would account for the reductions in LDL-C.

The serum and hepatic lipid concentrations were investigated in rats made nephrotic with a single intraperitoneal injection of cisplatin (6 mg kg(-1) b.wt.). The serum creatinine and urea concentrations were estimated as indices of nephrotoxicity, and the serum total bilirubin level as a liver function test. 3 The fasting serum total cholesterol, triglycerides (TG) and the cholesterol fractions associated with the various lipoproteins, as well as hepatic cholesterol and TG contents were also measured, following 5, 10 and 15 days from the cisplatin treatment. 4 The results revealed that on day 5 both serum creatinine and urea concentrations were significantly (P<0.01) increased, indicating the peak of nephrotoxicity, with no injurious effects on the liver as indicated by the unaltered serum bilirubin concentration. 5 The nephrotoxicity was accompanied by significant elevations in serum total cholesterol and TG concentrations by 49 and 42%, respectively, with significant (P < 0.05) correlations between the serum cholesterol and TG concentrations versus the serum urea (r=0.68 and r=0.60, respectively). Among the estimated lipoproteins, very low density lipoprotein (VLDL) cholesterol was severely increased to more than twofold with no severe changes in LDL- or HDL-cholesterol fractions. On day 5 the liver also showed significant accumulation of TG with no change in the cholesterol content. Animals killed 10 or 15 days post-cisplatin treatment had all the perturbed parameters returned to the normal levels. The present results indicated that rats exposed to a single cisplatin injection exhibit acute reversible nephrosis on day 5 which was accompanied by dyslipidaemia and accumulated liver TG.

The relations between the level of plasma nonesterified fatty acid (NEFA) and both the mass concentration and activity of the cholesteryl ester transfer protein (CETP) were studied in fasted normolipidemic subjects. Plasma NEFA correlated positively with both CETP mass concentration (r = .50; P < .01) and the transfer of cholesteryl ester from HDL toward plasma VLDL+LDL (CETHDL->>VLDL+LDL activity) (r = .46; P < .05) but not with the transfer of cholesteryl ester from LDL toward plasma HDL (CETLDL->>HDL activity) (r = .05; NS). The high binding capacity of albumin for NEFA was used to investigate whether lipoprotein-bound NEFAs were implicated in the modulation of the cholesteryl ester transfer reaction. As compared with nonsupplemented controls, the addition of an excess of fatty acid-free albumin (8 g/L) to total normolipidemic plasmas reduced CETHDL->>VLDL+LDL activity (18.3 +/- 5.5% versus 9.8 +/- 3.1%; P < .0001) but not CETLDL->>HDL activity (22.3 +/- 4.5% versus 23.3 +/- 5.1%; NS). Moreover, CETHDL->>VLD+LDL and CETLDL->>HDL activities correlated negatively when measured in native plasma (r = -.45; P < .05) but positively when measured in albumin-supplemented plasma (r = .40; P < .05). In long-term incubation experiments, lipoprotein-bound NEFA increased the net mass transfer of cholesteryl esters from HDL toward VLDL+LDL but reduced the net mass transfer of triglycerides in the opposite direction, from VLDL+LDL toward HDL. Taken together, data of the present study brought strong and concordant arguments in favor of a dual effect of plasma NEFA in modulating both the mass and the activity of CETP in vivo.

High-performance affinity chromatography (HPAC) was utilized to examine the binding of very low density lipoprotein (VLDL) with drugs, using R/S-propranolol as a model. These studies indicated that two mechanisms existed for the binding of R- and S-propranolol with VLDL. The first mechanism involved non-saturable partitioning of these drugs with VLDL, which probably occurred with the lipoprotein's non-polar core. This partitioning was described by overall affinity constants of 1.2 (±0.3) × 10(6) M(-1) for R-propranolol and 2.4 (±0.6) × 10(6) M(-1) for S-propranolol at pH 7.4 and 37 °C. The second mechanism occurred through saturable binding by these drugs at fixed sites on VLDL, such as represented by apolipoproteins on the surface of the lipoprotein. The association equilibrium constants for this saturable binding at 37 °C were 7.0 (±2.3) × 10(4) M(-1) for R-propranolol and 9.6 (±2.2) × 10(4) M(-1) for S-propranolol. Comparable results were obtained at 20 and 27 °C for the propranolol enantiomers. This work provided fundamental information on the processes involved in the binding of R- and S-propranolol to VLDL, while also illustrating how HPAC can be used to evaluate relatively complex interactions between agents such as VLDL and drugs or other solutes.

OBJECTIVE

Elevated plasma lipoprotein(a) [Lp(a)] is a significant risk factor for vascular disease. Standardization of Lp(a) mass measurement is complicated by the heterogeneity of apolipoprotein(a) [apo(a)]. We investigated whether Lp(a) cholesterol measurement, which is not influenced by apo(a) size, is a viable alternative to measuring Lp(a) mass.

METHODS

Plasma Lp(a) cholesterol was measured electrophoretically, with and without ultracentrifugation, and results were compared to each other and to immunoturbidimetrically measured Lp(a) mass in 470 subjects.

RESULTS

Ultracentrifuged and whole plasma Lp(a) cholesterol levels demonstrated high correlation (R = 0.964). All samples with detectable >>/=2.0 mg/dl) Lp(a) cholesterol had Lp(a) mass >30 mg/dl (the clinically relevant cutpoint), while 59 samples with Lp(a) mass >30 mg/dl did not have detectable Lp(a) cholesterol.

CONCLUSIONS

Lp(a) cholesterol can be measured in whole plasma without interference from VLDL lipoproteins. The relative clinical merits of measuring Lp(a) cholesterol vs. Lp(a) mass or both in combination deserves investigation.