Effect of omega-3 fatty acid supplementation on arterial elasticity in patients with familial hypercholesterolaemia on statin therapy.

BACKGROUND AND AIMS: Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated. METHOD AND RESULTS: We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P < 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration. CONCLUSIONS: ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.com/NCT01577056.

Effect of niacin on triglyceride-rich lipoprotein apolipoprotein B-48 kinetics in statin-treated patients with type 2 diabetes.

AIM: To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). METHODS: A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. RESULTS: In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). CONCLUSIONS: ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.

Association between skeletal muscle fat content and very-low-density lipoprotein-apolipoprotein B-100 transport in obesity: effect of weight loss.

AIMS: Ectopic deposition of fat in skeletal muscle is a feature of metabolic syndrome, but its specific association with very-low-density lipoprotein (VLDL)-apolipoprotein (apo) B-100 metabolism remains unclear. METHODS: We examined the association between skeletal muscle fat content and VLDL-apoB-100 kinetics in 25 obese subjects, and the responses of these variables to weight loss. The fat contents of liver, abdomen and skeletal muscle were determined by magnetic resonance imaging, and VLDL-apoB-100 kinetics were assessed using stable isotope tracers. RESULTS: In obese subjects who were insulin sensitive (homeostasis model assessment, HOMA, score ≤ 2.6, n = 12), skeletal muscle fat content was significantly associated with hepatic fat content (r = 0.636), energy intake (r = 0.694), plasma triglyceride (r = 0.644), apoB-100 (r = 0.529), glucose (r = 0.622), VLDL-apoB-100 concentrations (r = 0.860), VLDL-apoB-100 fractional catabolic rate (FCR; r = -0.581) and VLDL-apoB-100 secretion rate (r = 0.607). These associations were not found in obese subjects who were insulin resistant (HOMA score >2.6, n = 13). Of these 25 subjects, 10 obese subjects underwent a 16-week weight loss program. The low-fat diet achieved significant reduction (p < 0.05) in body weight, visceral and subcutaneous fat areas, liver and skeletal muscle fat, energy intake, triglyceride, insulin, HOMA score, VLDL-apoB100 concentrations and VLDL-apoB100 secretion rate. The percentage reduction of skeletal muscle fat with weight loss was significantly associated with the corresponding changes in VLDL-apoB100 concentration (r = 0.770, p = 0.009) and VLDL-apoB-100 secretion (r = 0.682, p = 0.030). CONCLUSIONS: Skeletal muscle fat content is associated with VLDL-apoB-100 transport. Weight loss lowers skeletal muscle fat and VLDL-apoB-100 secretion.

Atorvastatin plus omega-3 fatty acid ethyl ester decreases very-low-density lipoprotein triglyceride production in insulin resistant obese men.

AIM: To test the effect of atorvastatin (ATV) and ATV plus ω-3 FAEEs on VLDL-TG metabolism in obese, insulin resistant men. METHODS: We carried out a 6-week randomized, placebo-controlled study to examine the effect of ATV (40 mg/day) and ATV plus ω-3 FAEEs (4 g/day) on VLDL-TG metabolism in 36 insulin resistant obese men. VLDL-TG kinetics were determined using d5 -glycerol, gas chromatography-mass spectrometry and compartmental modelling. RESULTS: Compared with the placebo, ATV significantly decreased VLDL-TG concentration (-40%, p < 0.001) by increasing VLDL-TG fractional catabolic rate (FCR) (+47%, p < 0.01). ATV plus ω-3 FAEEs lowered VLDL-TG concentration to a greater degree compared with placebo (-46%, p < 0.001) or ATV monotherapy (-13%, p = 0.04). This was achieved by a reduction in VLDL-TG production rate (PR) compared with placebo (-32%, p = 0.008) or ATV (-20%, p = 0.03) as well as a reciprocal increase in VLDL-TG FCR (+42%, p < 0.05) compared with placebo. CONCLUSION: In insulin resistant, dyslipidaemic, obese men, ATV improves VLDL-TG metabolism by increasing VLDL-TG FCR. The addition of 4 g/day ω-3 FAEE to statin therapy provides further TG-lowering by lowering VLDL-TG PR.

The effect of fenofibrate on HDL cholesterol and HDL particle concentration in postmenopausal women on tibolone therapy.

BACKGROUND: Low high-density lipoprotein (HDL) cholesterol and particle concentration are risk factors for coronary heart disease in women. Tibolone lowers HDL cholesterol and HDL particle concentration, an effect that could be reversed by the peroxisome proliferator-activator receptor-α agonist fenofibrate. OBJECTIVE: To assess the effects of fenofibrate on plasma HDL particles in postmenopausal women taking tibolone therapy. DESIGN AND PARTICIPANTS: Randomized crossover study conducted in a women's health clinic. Fourteen postmenopausal women taking tibolone 2.5 mg daily for menopausal symptoms were randomized to either fenofibrate 160 mg daily or no treatment for 8 weeks, followed by a 3-week wash-out for fenofibrate and then crossed over to alternate therapy for another 8 weeks. The main outcome measure was changes in plasma HDL cholesterol concentration, apoA-I and apoA-II, LpA-I and LpA-I-A-II. RESULTS: After 8 weeks of fenofibrate therapy, there was no change in HDL cholesterol, 1.13 ± 0.06 v 1.16 ± 0.06 mmol/l (P = 0.47) or apoA-I, 1.19 ± 0.05 v 1.20 ± 0.05 g/l (P = 0.23). LpA-I fell significantly 0.35 ± 0.03 v 0.29 ± 0.02 (P = 0.02) but there was a rise in apoA-II, 0.35 ± 0.01 v 0.39 ± 0.01 g/l (P = 0.01). There was a significant fall in total cholesterol, triglycerides, low-density lipoprotein cholesterol and apoB. CONCLUSION: In women taking tibolone, fenofibrate increases plasma apoA-II concentration and effects a redistribution of HDL subfractions but does not correct tibolone-induced changes in HDL cholesterol or HDL particle concentration. The mechanism and significance of this require further investigation.

Effect of weight loss on markers of triglyceride-rich lipoprotein metabolism in the metabolic syndrome.

BACKGROUND: Hypertriglyceridaemia, a consistent feature of dyslipidaemia in the metabolic syndrome (MetS), is related to the extent of abdominal fat mass and altered adipocytokine secretion. We determined the effect of weight loss by dietary restriction on markers of triglyceride-rich lipoprotein (TRL) metabolism and plasma adipocytokines. DESIGN: Thirty-five men with MetS participated in a 16 week randomized controlled dietary intervention study. Apolipoprotein (apo) C-III, apoB-48, remnant-like particle (RLP)-cholesterol, total adiponectin, high-molecular weight (HMW) adiponectin, and retinol-binding protein-4 (RBP-4) concentrations were measured using immunoassays. RESULTS: Compared with weight maintenance (n = 15), weight loss (n = 20) significantly decreased body weight, plasma insulin, triglycerides, total cholesterol, low-density lipoprotein (LDL)-cholesterol and lathosterol (P < 0.05). Weight loss also decreased plasma concentrations of apoC-III (-33%), apoB-48 (-37%), very low-density lipoprotein (VLDL)-apoB (-43%), RLP-cholesterol (-48%), and RBP-4 (-20%), and significantly increased plasma total (+20%) and HMW-adiponectin (+19%) concentrations. In the weight loss group, reduction in plasma apoC-III was associated (P < 0.05) with reduction in plasma apoB-48, VLDL-apoB, RLP-cholesterol and triglycerides. Increase in total adiponectin was associated (P < 0.05) with the reduction in plasma VLDL-apoB and triglycerides. The changes in HMW-adiponectin and RBP-4 were not associated with changes in plasma apoB-48, apoC-III, VLDL-apoB, RLP-cholesterol or triglycerides. In multiple regression analysis including changes in visceral fat, insulin and total adiponectin concentrations, the fall in plasma apoC-III concentration was an independent predictor of the reductions in plasma apoB-48, VLDL-apoB, RLP-cholesterol and triglycerides concentrations. CONCLUSIONS: In men with MetS, weight loss decreases the plasma concentrations of apoB-48, VLDL-apoB, RLP-cholesterol and triglycerides. This effect could partly relate to concomitant changes in plasma apoC-III and adiponectin concentrations that accelerate the catabolism of TRLs.

Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin.

OBJECTIVE: The effects of the statin, rosuvastatin on indices of reverse cholesterol transport were studied in a randomized, placebo-controlled, cross-over trial in 25 overweight subjects with defined metabolic syndrome. RESULT: Four weeks' treatment with 40 mg/day rosuvastatin significantly reduced levels of plasma cholesterol (44%), LDL cholesterol (60%) and triglyceride (38%). HDL cholesterol (mean [S.D.]) rose (0.97[0.17] to 1.05[0.17]mmol/L; P<0.05) and the LpA-I component of HDL from 39[7] to 45[9]mg/dL (P<0.05). LCAT activity fell (0.55[0.13] to 0.35[0.07]nmol/mL/h; P<0.05); CETP activity and mass fell from 89[13] to 80[11]nmol//L/h and from 1.66[0.57] to 1.28[0.41]mug/mL respectively, (P<0.05). Cholesterol efflux in vitro (to plasmas from THP-1 activated cells) fell from 7.1[1.8]% (placebo) to 6.2[1.7]% (rosuvastatin); P<0.05, but when plasmas depleted of apoB lipoproteins were studied, the difference in efflux was no longer statistically significant. During placebo efflux was paradoxically inversely correlated with HDL-C (P=0.016) and LpA-I (P=0.035) concentrations but these correlations were absent after rosuvastatin. CONCLUSIONS: The data suggest possible HDL dysfunctionality in subjects with metabolic syndrome. The reduced capacity of plasmas following statin treatment to stimulate cholesterol efflux in vitro occurred in association with reduction in apoB lipoproteins and reduced activities of CETP and LCAT, and despite increased levels of HDL cholesterol.

Measurement of liver fat by magnetic resonance imaging: Relationships with body fat distribution, insulin sensitivity and plasma lipids in healthy men.

AIM: We compared the use of magnetic resonance imaging (MRI) as a test for liver fat content (LFAT) with proton magnetic resonance spectroscopy (MRS) and investigated its relationship with body fat distribution, insulin sensitivity, plasma lipids and lipoproteins. METHODS: LFAT was quantified by MRI and MRS in 17 free-living, healthy men with a wide range of body mass indexes. Fasting adiponectin was measured by immunoassay and insulin resistance by homeostasis assessment (HOMA) score. Intraperitoneal, retroperitoneal, anterior subcutaneous and posterior subcutaneous abdominal adipose tissue masses (ATMs) were determined by MRI. RESULTS: Measurements of LFAT by MRI and MRS were highly correlated (r = 0.851, p < 0.001). In univariate regression analysis, LFAT by MRI was also significantly correlated with plasma triglycerides (TGs), insulin, HOMA score, carbohydrate intake and the masses of all abdominal adipose tissue compartments (p < 0.05). LFAT was inversely correlated with plasma adiponectin (r = -0.505, p < 0.05). In multivariate linear regression analysis including plasma adiponectin and age, intraperitoneal ATM was an independent predictor of LFAT (beta-coefficient = 0.587, p = 0.024). Moreover, intraperitoneal ATM was also an independent predictor of HOMA score after adjusting for LFAT, plasma adiponectin and age (beta-coefficient = 0.810, p = 0.010). Conversely, LFAT was a significant predictor of plasma TG concentration after adjusting for adiponectin, intraperitoneal ATM, HOMA and age (beta-coefficient = 0.751, p = 0.007). Similar findings applied with LFAT measured by MRS. CONCLUSIONS: These data suggest that MRI is as good as MRS to quantify liver fat content. Our data also suggest that liver fat content could link intraabdominal fat with insulin resistance and dyslipidaemia.

High-density lipoprotein apolipoprotein A-I kinetics: comparison of radioactive and stable isotope studies.

To compare the kinetic determinants of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) concentration in lean normolipidaemic subjects using radioisotope and stable isotope studies. We pooled data from 16 radioisotope and 13 stable isotope studies to investigate the kinetics of apoA-I in lean normolipidemic individuals. We also examined the associations of HDL kinetic parameters with age, sex, body mass index (BMI) and concentrations of apoA-I, triglycerides, HDL cholesterol and low-density lipoprotein (LDL) cholesterol. Lean subjects from radioisotope and stable isotope studies were matched for age, gender, BMI and lipid profile. The apoA-I concentration was significantly lower in the radioisotope group than the stable isotope group (P = 0.031). There was no significant difference in HDL apoA-I fractional catabolic rate (FCR) and production rate (PR) between the groups. In the radioisotope group, HDL apoA-I FCR was significantly associated with apoA-I and HDL cholesterol concentrations (r = -0.681, P < 0.001 and r = -0.542, P < 0.001, respectively), whereas in the stable isotope group, only HDL apoA-I PR was significantly associated with apoA-I concentration (r = 0.455, P = 0.004). Our findings suggest that HDL apoA-I FCR is the primary determinant of apoA-I concentrations in lean subjects in studies using radiotracer techniques. By contrast, HDL apoA-I PR is the primary determinant of apoA-I concentration in lean subject in studies employing stable isotope methods. These discrepancies may be reconciled by differences in methodologies and/or study population characteristics.

Fish oils, phytosterols and weight loss in the regulation of lipoprotein transport in the metabolic syndrome: lessons from stable isotope tracer studies.

1. Dyslipoproteinaemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. It is characterized by high plasma concentrations of triglyceride-rich and apolipoprotein (apo) B-containing lipoproteins, with depressed concentrations of high-density lipoprotein (HDL). Dysregulation of lipoprotein metabolism in these subjects may be due to a combination of overproduction of very-low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles and increased catabolism of HDL apoA-I particles. 2. Nutritional interventions may favourably alter lipoprotein transport in the metabolic syndrome. We review our collaborative studies, using stable isotopes and compartmental modelling, of the kinetic effects of fish oils, plant sterols (phytosterols) and weight reduction on the dyslipoproteinaemia in this disorder. 3. Fish oil supplementation diminished hepatic secretion of VLDL-apoB and enhanced conversion of VLDL to low-density lipoprotein (LDL)-apoB, without altering catabolism. 4. Plant sterols (phytosterols) did not have a significant effect on plasma concentrations of lipids and lipoprotein or the kinetics of apoB and apoA-I. 5. Modest weight reduction optimally decreased plasma triglyceride and LDL-cholesterol via reduction in hepatic apoB secretion and reciprocal upregulation of LDL catabolism. 6. The scope and potential of future studies using stable isotope tracers is discussed.

Effect of an acute hyperinsulinaemic clamp on post-prandial lipaemia in subjects with insulin resistance.

BACKGROUND: Obese, insulin-resistant individuals have raised levels of intestinal and hepatic lipoproteins. Insulin decreases the production of hepatic lipoproteins in vivo and so this study aimed to investigate whether an acute hyperinsulinaemic, euglycaemic clamp could correct fasting and post-prandial dyslipidaemia. SUBJECTS AND METHODS: In a randomized, cross-over design, post-prandial lipaemia was compared in subjects infused either with insulin to achieve a steady-state concentration of 100 mU L(-1) or with saline. Nine obese (Body Mass Index > 26 kg m(-2); waist : hip > 1.0) insulin-resistant (Homeostatic Model Assessment score > 2.0) male subjects were given an oral fat load 3 h after the infusions began, and sampling continued for 6 h. Plasma apoB-48, triglyceride and nonesterified fatty acid (NEFA) were measured hourly. RESULTS: Average steady-state serum insulin levels during the hyperinsulinaemic clamp were 123 +/- 4.4 mU L(-1). A paired analysis showed no net effect of insulin on post-prandial chylomicron metabolism when calculated as the (apoB-48) incremental area under the curve (IAUC). However, there was a trend towards a delay in the apoB-48 peak, consistent with possible changes in the rates of chylomicron biogenesis, lipolysis and/or clearance. Similarly, post-prandial lipaemia (depicted as triglyceride IAUC) was similar for subjects infused with insulin or saline, but the peak post-prandial response was delayed during insulin infusion. The NEFA were rapidly decreased by 83% after 3 h of insulin infusion. CONCLUSIONS: In obesity and insulin resistance, short-term changes in plasma insulin do not appreciably exert a regulatory effect on exogenously-derived post-prandial lipoproteins. The data suggest that hyperchylomicronaemia in insulin-resistant subjects is a result of chronic aberrations in insulin-mediated regulation of post-prandial lipid metabolism.

Effect of inhibiting cholesteryl ester transfer protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma: in vivo studies in rabbits.

OBJECTIVE: Inhibitors of cholesteryl ester transfer protein (CETP) have been developed as potential anti-atherogenic agents. Theoretically, however, they may be pro-atherogenic by blocking one of the pathways for removing high-density lipoprotein (HDL) cholesteryl esters (CE) from plasma in the final step of reverse cholesterol transport. Here we describe how CETP inhibition in rabbits impacts on the kinetics of HDL CE transport in plasma. METHODS AND RESULTS: Administration of a CETP inhibitor reduced CETP activity by 80% to 90% and doubled the HDL cholesteryl ester concentration. Multi-compartmental analysis was used to determine HDL CE kinetics in CETP-inhibited and control rabbits after injection of tracer amounts of both native and reconstituted HDL labeled with 3H in the CE moiety. In control rabbits, HDL CE was removed from plasma by both a direct pathway and an indirect pathway after transfer of HDL CE to the very-low-density lipoprotein/low-density lipoprotein fraction. In CETP-inhibited rabbits there was an almost complete block in removal via the indirect pathway. This did not compromise the overall removal of HDL CE from plasma, which was not different in control and inhibited animals. CONCLUSIONS: Inhibiting CETP in rabbits does not compromise the removal of HDL CE from plasma.

Does pravastatin increase chylomicron remnant catabolism in postmenopausal women with type 2 diabetes mellitus?

OBJECTIVE: We investigated the effects of pravastatin on chylomicron remnant catabolism measured with a 13C stable isotope breath test and plasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol in postmenopausal women with type 2 diabetes mellitus. PATIENTS AND MEASUREMENTS: Nineteen postmenopausal women with type 2 diabetes were randomized to receive 40 mg/day pravastatin or no treatment for 6 weeks followed by a 2-week washout period, and crossed over for a further 6 weeks. Fractional catabolic rate (FCR) of a chylomicron remnant-like emulsion was determined from 13CO2 enrichment in the breath and plasma using isotope-ratio mass spectrometry and multicompartmental modelling. Plasma apo B-48 and RLP-cholesterol concentrations were also measured as static markers of chylomicron remnant metabolism. RESULTS: Pravastatin significantly reduced plasma concentrations of cholesterol (5.9 +/- 0.3 vs. 4.8 +/- 0.2 mmol/l; P < 0.001), low density lipoprotein (LDL)-cholesterol (3.5 +/- 0.2 vs. 2.6 +/- 0.2 mmol/l; P < 0.001), triglyceride (2.1 +/- 0.3 vs. 1.7 +/- 0.2 mmol/l; P = 0.017), non-high density lipoprotein (HDL)-cholesterol (4.4 +/- 0.3 vs. 3.3 +/- 0.2 mmol/l; P < 0.001), lathosterol/total cholesterol ratio (2.6 +/- 0.2 vs. 2.0 +/- 0.3, P = 0.035), apo B-100 (1.1 +/- 0.1 vs. 0.8 +/- 0.1 g/l; P = 0.001), apo B-48 (4.8 +/- 0.9 vs. 3.3 +/- 0.6 mg/l; P = 0.016), and RLP-cholesterol (31.4 +/- 8.2 vs. 18.6 +/- 4.6 mg/dl; P = 0.024). Pravastatin was also associated with an increase in sitosterol/total cholesterol ratio (2.8 +/- 0.3 vs. 3.1 +/- 0.3, P = 0.029). Chylomicron remnant-like emulsion catabolism was not, however, significantly altered by pravastatin estimated by either breath or plasma clearance measurements. CONCLUSIONS: In postmenopausal women, pravastatin decreases plasma concentrations of remnant lipoproteins by a mechanism that may relate chiefly to inhibition of remnant production, but this requires further evaluation.

Association of adiponectin and resistin with adipose tissue compartments, insulin resistance and dyslipidaemia.

AIM: In this study, we investigated the association of plasma adiponectin and resistin concentrations with adipose tissue compartments in 41 free-living men with a wide range of body mass index (22-35 kg/m(2)). METHODS: Using enzyme immunoassays, plasma adiponectin and resistin were measured. Intraperitoneal, retroperitoneal, subcutaneous abdominal and posterior subcutaneous abdominal adipose tissue masses (IPATM, RPATM, SAATM and PSAATM, respectively) were determined using magnetic resonance imaging. Total adipose tissue mass (TATM) was measured using bioelectrical impedance. Insulin resistance was estimated with the help of homeostasis model assessment (HOMA) score. RESULTS: In univariate regression, plasma adiponectin levels were inversely related to IPATM (r = -0.389, p < 0.05), SAATM (r = -0.500, p < 0.001), PSAATM (r = -0.502, p < 0.001), anterior SAATM (r = -0.422, p < 0.01) and TATM (r = -0.421, p < 0.01). In multiple regression models, adiponectin was chiefly correlated with PSAATM. Plasma adiponectin concentrations were also inversely correlated with HOMA score (r = -0.540, p < 0.001) and triglyceride (r = -0.632, p < 0.001), and positively correlated with high-density lipoprotein cholesterol (r = 0.508, p < 0.001). There were no significant correlations between resistin levels and adipose tissue masses, insulin resistance or dyslipidaemia. CONCLUSIONS: In men, total body fat is significantly correlated with plasma adiponectin, but not with plasma resistin levels. Low plasma adiponectin levels appear to be chiefly determined by the accumulation of posterior subcutaneous abdominal fat mass, as opposed to intra-abdominal fat, and are strongly predictive of insulin resistance and dyslipidaemia.

ATP-binding cassette transporter G8 gene as a determinant of apolipoprotein B-100 kinetics in overweight men.

OBJECTIVE: We examined the influence of genetic variation of the ATP-binding cassette (ABC) transporter G8 on apolipoprotein B (apoB) kinetics in overweight/obese men. METHODS AND RESULTS: Very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) apoB kinetics were determined in 47 men (body mass index 32+/-3 kg/m2) using stable isotope and multicompartmental modeling to estimate production rate (PR), fractional catabolic rate (FCR), and VLDL to LDL-apoB conversion. Relative to the wild-type (400TT), subjects carrying the ABCG8 400K allele had significantly decreased plasma concentrations of triglycerides, sitosterol, and campesterol, lower PR of VLDL-apoB, and higher VLDL to LDL-apoB conversion (P<0.05). The PR and FCR of LDL-apoB were also significantly higher with 400K allele (P<0.05). No association was found with ABCG8 D19H. Compared with APOE2 or APOE3, APOE4 carriers had significantly higher plasma LDL-cholesterol concentrations and lower LDL-apoB FCR. During multiple regression analysis including age, homeostasis model assessment score, plasma concentrations of sitosterol, and lathosterol, ABCG8 and apoE genotypes were independent determinants of VLDL-apoB PR and LDL-apoB FCR, respectively (P<0.05). CONCLUSIONS: Variation in the ABC transporter G8 appears to independently influence the metabolism of apoB-containing lipoproteins in overweight/obese subjects. This may have therapeutic implications for the management of dyslipidemia in these subjects.

In vivo metabolism of LDL subfractions in patients with heterozygous FH on statin therapy: rebound analysis of LDL subfractions after LDL apheresis.

LDL can be subfractionated into buoyant (1.020-1.029 g/ml(-1)), intermediate (1.030-1.040 g/ml(-1)), and dense (1.041-1.066 g/ml(-1)) LDLs. We studied the rebound of these LDL-subfractions after LDL apheresis in seven patients with heterozygous familial hypercholesterolemia (FH) regularly treated by apheresis (58 +/- 9 years, LDL-cholesterol = 342 +/- 87 mg/dl(-1), triglycerides = 109 +/- 39 mg/dl(-1)) and high-dose statins. Apolipoprotein B (apoB) concentrations were measured in LDL subfractions immediately after and on days 1, 2, 3, 5, and 7 after apheresis. Compartmental models were developed to test three hypotheses: 1) that dense LDLs are derived from the delipidation of buoyant and intermediate LDLs (model A); 2) that dense LDLs are generated directly from LDL-precursors (model B); or 3) that a model combining both pathways (model C) is necessary to describe the metabolism of dense LDLs. In all models, it was assumed that apoB production and fractional catabolic rate (FCR) did not change with apheresis. Apheresis decreased buoyant, intermediate, and dense LDL-apoB by 60 +/- 12%, 67 +/- 5%, and 69 +/- 11%, respectively. Models B and C, but not model A, described the rebound data. The model with the greatest biological plausibility (model C) was used to estimate metabolic parameters. FCR was 1.05 +/- 0.86 d(-1), 0.48 +/- 0.11 d(-1), and 0.69 +/- 0.24 d(-1) for buoyant, intermediate, and dense LDLs, respectively. Dense LDL production was 17.3 +/- 0.2 mg/kg(-1)/d(-1), 58% of which was derived directly from LDL precursors (VLDL, IDL, or direct secretion), while 42% was derived from buoyant and intermediate LDLs. Thus, our data indicate that in statin-treated patients with heterozygous FH dense LDLs originate from two sources. Whether this is also valid in other metabolic situations (with predominant small, dense LDLs) remains to be determined.

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans.

AIMS/HYPOTHESIS: Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding. METHODS: Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined. RESULTS: Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells. CONCLUSIONS/INTERPRETATION: Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.

Four novel mutations in APOB causing heterozygous and homozygous familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a rare codominant disorder of lipoprotein metabolism characterized by low levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B. Heterozygotes for FHBL have less-than-half normal LDL-cholesterol and apoB concentrations, whereas homozygotes have extremely low or undetectable LDL-cholesterol and apoB levels. These reductions in LDL-cholesterol and apoB have been suggested to provide FHBL subjects with resistance to atherosclerosis. FHBL can be caused by mutations in the APOB gene on chromosome 2. We present four novel mutations and one previously described mutation in APOB causing FHBL in five families. Immunoblotting and DNA sequencing were used to characterize the novel mutation apoB-40.3 (c.5564_5565insC) and the previously reported mutation apoB-80.5 (c.11040T>G). The apoB-6.9 (c.1018_1025del) and apoB-25.8 (c.3600T>A) mutations were identified by DNA sequence analysis, as variants shorter than apoB-31 are not detectable in plasma. A fifth mutation, the splice variant c.82+1G>A, was identified by sequencing and was found in a homozygous subject. In approximately 50% of the FHBL subjects, plasma alanine aminotransferase concentrations were mildly increased, suggestive of fatty liver. All affected FHBL subjects had low to low-normal serum vitamin E concentrations, highlighting the important and recognized relationship between lipid and vitamin E concentrations.

Effect of a statin on hepatic apolipoprotein B-100 secretion and plasma campesterol levels in the metabolic syndrome.

OBJECTIVE: We aimed to study the effect of atorvastatin, a statin, on cholesterol synthesis and absorption and VLDL-apoB metabolism in obese men with the metabolic syndrome. METHODS: A total of 25 dyslipidaemic obese men were randomized to atorvastatin (n=13) (40 mg/day) or matching placebo (n=12) for 6 weeks. Hepatic secretion and fractional catabolic rate (FCR) of VLDL-apoB was measured using an intravenous bolus of d(3)-leucine before and after treatment. ApoB isotopic enrichment was measured using GCMS and multicompartmental modelling. Plasma lathosterol: cholesterol and campesterol:cholesterol ratios were determined to assess cholesterol synthesis and cholesterol absorption, respectively. RESULTS: Compared with placebo, atorvastatin significantly decreased (P<0.05) total cholesterol, triglyceride, LDL-cholesterol and VLDL-apoB. Plasma lathosterol:cholesterol ratio decreased from 26.4+/-2.4 to 8.8+/-0.8, while the campesterol:cholesterol ratio increased from 26.5+/-4.4 to 38.6+/-5.8 (P<0.01). Atorvastatin also increased VLDL-apoB FCR from 3.82+/-0.33 to 6.30+/-0.75 pools/day (P<0.01), but did not significantly alter VLDL-apoB secretion (12.8+/-1.7 to 13.8+/-2.0 mg/kg/day). CONCLUSIONS: In obesity, atorvastatin inhibits cholesterogenesis but increases intestinal cholesterol absorption. The increased cholesterol absorption may counteract the inhibitory effect on hepatic VLDL-apoB secretion, but it does not apparently influence enhanced catabolism of VLDL-apoB.

Waist circumference, waist-to-hip ratio and body mass index as predictors of adipose tissue compartments in men.

BACKGROUND: The accumulation of fat in visceral and posterior subcutaneous adipose tissue compartments is highly correlated with the metabolic abnormalities that contribute to increased risk of diabetes mellitus and cardiovascular disease. AIM: To determine which of waist circumference (WC), waist-to-hip ratio (WHR) and body mass index (BMI) was the best predictor of intraperitoneal and posterior subcutaneous abdominal adipose tissue mass in men. METHODS: We studied 59 free-living men with a wide range of BMI. WC, WHR and BMI were determined using standard methods. Intraperitoneal, retroperitoneal, anterior subcutaneous and posterior subcutaneous abdominal adipose tissue masses (IPATM, RPATM, ASAATM and PSAATM, respectively) were quantified using magnetic resonance imaging. RESULTS: In univariate regression analysis, WC, WHR and BMI were all significantly and positively correlated (all p < 0.05) with IPATM, RPATM, ASAATM and PSAATM. To assess the relative strength of these associations, we used non-nested regression models. There was no significant difference between WC and WHR in predicting IPATM and RPATM; WC was a stronger predictor of ASAATM (p < 0.001) and PSAATM (p < 0.001) than WHR; WC was also a stronger predictor of IPATM (p = 0.042) and RPATM (p = 0.045) than BMI, but the relative strengths of WC and BMI in predicting ASSATM and PSAATM did not different significantly (p > 0.05); there was no significant difference between BMI and WHR in predicting IPATM and RPATM (p>0.05), but BMI was a stronger predictor of ASAATM (p = 0.036) and PSAATM (p < 0.001) than WHR. DISCUSSION: In men WC is the anthropometric index that most uniformly predicts the distribution of adipose tissue among several fat compartments in the abdominal region, there apparently being little value in measuring WHR or BMI.