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Objective: The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with LDL or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increase to assess whether VLDL-C is a valid proxy for VLDL-apoB., Methods: We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed this data in quartiles of TG or apoB., Results: There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80 % of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90 % of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high., Conclusions: In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: The substitution of monounsaturated acids (MUFAs) for saturated fatty acids (SFAs) is recommended for cardiovascular disease prevention but its impact on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains largely unknown., Objectives: This study aimed to evaluate the impact of substituting MUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo)B-containing lipoproteins and on the plasma lipidomic profile in adults with IR-induced dyslipidemia., Methods: Males and females with dyslipidemia associated with IR (n = 18) were recruited for this crossover double-blind randomized controlled trial. Subjects consumed, in random order, a diet rich in SFAs (SFAs: 13.4%E; MUFAs: 14.4%E) and a diet rich in MUFAs (SFAs: 7.1%E; MUFAs: 20.7%E) in fully controlled feeding conditions for periods of 4 wk each, separated by a 4-wk washout. At the end of each diet, fasting plasma samples were taken together with measurements of the in vivo kinetics of apoB-containing lipoproteins., Results: Substituting MUFAs for SFAs had no impact on triglyceride-rich lipoprotein apoB-48 fractional catabolic rate (FCR) (Δ = -8.9%, P = 0.4) and production rate (Δ = 0.0%, P = 0.9), although it decreased very low-density lipoprotein apoB-100 pool size (PS) (Δ = -22.5%; P = 0.01). This substitution also reduced low-density lipoprotein cholesterol (LDL-C) (Δ = -7.0%; P = 0.01), non-high-density lipoprotein cholesterol (Δ = -2.5%; P = 0.04), and LDL apoB-100 PS (Δ = -6.0%; P = 0.05). These differences were partially attributed to an increase in LDL apoB-100 FCR (Δ = +1.6%; P = 0.05). The MUFA diet showed reduced sphingolipid concentrations and elevated glycerophospholipid levels compared with the SFA diet., Conclusions: This study demonstrated that substituting dietary MUFAs for SFAs decreases LDL-C levels and LDL PS by increasing LDL apoB-100 FCR and results in an overall improved plasma lipidomic profile in individuals with IR-induced lipidemia., Trial Registration: This trial was registered as clinicaltrials.gov as NCT03872349., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m 2 , plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = -0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = -0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to validate an automated self-administered 24-hour dietary recall web application (R24W) against recovery biomarkers for sodium, potassium and protein intakes and to identify individual characteristics associated with misreporting in a sample of 61 men and 69 women aged 20-65 years from Québec City, Canada. Each participant completed 3 dietary recalls using the R24W, provided two 24-hour urinary samples and completed questionnaires to document psychosocial factors. Mean reported intakes were 2.2%, 2.1% and 5.0% lower than the urinary reference values, respectively, for sodium, potassium and proteins (significant difference for proteins only ( p = 0.04)). Deattenuated correlations between the self-reported intake and biomarkers were significant for sodium ( r  = 0.48), potassium ( r  = 0.56) and proteins ( r  = 0.68). Cross-classification showed that 39.7% (sodium), 42.9% (potassium) and 42.1% (proteins) of participants were ranked into the same quartile with both methods and only 4.8% (sodium), 3.2% (potassium) and 0.8% (proteins) were ranked in opposite quartiles. Lower body esteem related to appearance was associated with sodium underreporting in women ( r  = 0.33, p = 0.006). No other individual factor was found to be associated with misreporting. These results suggest that the R24W has a good validity for the assessment of sodium, potassium and protein intakes in a sample of French-speaking adults. Novelty: The validity of an automated self-administered 24-hour dietary recall web application named the R24W was tested using urinary biomarkers. According to 7 criteria, the R24W was found to have a good validity to assess self-reported intakes of sodium, potassium and proteins.

Background: Determinants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH., Methods: A CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected., Results: A total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P  = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P  = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P  = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P  = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P  = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P  = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P  = 0.05)., Conclusions: In individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Background: Evidence suggests that pathophysiological conditions such as obesity and type 2 diabetes (T2D) are associated with morphologic and metabolic alterations in the small intestinal mucosa. Exploring these alterations generally requires invasive methods, limiting data acquisition to subjects with enteropathies or undergoing bariatric surgery. We aimed to evaluate small intestine epithelial cell homeostasis in a cohort of men covering a wide range of adiposity and glucose homoeostasis statuses., Methods: Plasma levels of citrulline, a biomarker of enterocyte mass, and I-FABP, a biomarker of enterocyte death, were measured by UHPLC‑MS and ELISA in 154 nondiabetic men and 67 men with a T2D diagnosis., Results: Plasma citrulline was significantly reduced in men with insulin resistance and T2D compared to insulin sensitive men. Decreased citrulline levels were, however, not observed in men with uncontrolled metabolic parameters during T2D. Plasma I-FABP was significantly higher in men with T2D, especially in presence of uncontrolled glycemic and lipid profile parameters. Integration of both parameters, which estimate enterocyte turnover, was associated with glucose homeostasis as well as with T2D diagnosis. Differences in biomarkers levels were independent of age and BMI and glucose filtration rates., Conclusions: Our study supports a decreased functional enterocyte mass and an increased enterocyte death rate in presence of metabolic alterations but emphasizes that epithelial cell homeostasis is especially altered in presence of severe insulin resistance and T2D. The marked changes in small intestine cellularity observed in obesity and diabetes are thus suggested to be part of gut dysfunctions, mainly at an advanced stage of the disease., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Introduction: In July 2013, a train derailment caused the death of 47 people and destroyed the downtown area in the city of Lac-Mégantic (Quebec, Canada). This tragedy had several impacts on this small community. Method: Three years after this disaster, we used a representative population-based survey conducted among 800 adults (including 265 seniors aged 65 or above) to assess the physical and mental health of seniors. Results: Several differences were observed in seniors' physical and mental health based on their level of exposure to the tragedy. Nearly half of seniors highly exposed to the train derailment (41.7%) believe that their health has deteriorated in the past 3 years. The majority of seniors highly exposed to the train derailment (68.7%) also show symptoms of posttraumatic stress disorders. Seniors highly or moderately exposed to the tragedy were also more likely to have found positive changes in their personal and social life as compared with nonexposed seniors. Discussion: A technological disaster such as a train derailment still had negative impacts on seniors' physical and mental health 3 years later. Conclusion: Public health authorities must tailor prevention and promotion programs to restore health and well-being in this population., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Type III hyperlipoproteinemia is a highly atherogenic dyslipoproteinemia characterized by hypercholesterolemia and hypertriglyceridemia due to markedly increased numbers of cholesterol-enriched chylomicron and very-low-density lipoprotein (VLDL) remnant lipoprotein particles. Type III can be distinguished from mixed hyperlipidemia based on a simple diagnostic algorithm, which involves total cholesterol, triglycerides, and apolipoprotein B (apoB). However, apoB is not measured routinely., Objective: The objective of the present study was to determine if patients with type III could be distinguished from mixed hyperlipidemia based on lipoprotein lipids., Methods: Classification was based first on total cholesterol and triglyceride and then on the apoB diagnostic algorithm using apoB plus total cholesterol plus triglycerides, and validated by sequential ultracentrifugation. Four hundred and forty normals, 637 patients with hypertriglyceridemia, and 714 with hypertriglyceridemia and hypercholesterolemia were studied. Plasma lipoproteins were separated by sequential ultracentrifugation and heparin-manganese precipitation. Cholesterol, triglyceride, and apoB were measured in plasma and isolated lipoprotein fractions., Results: Of the 1351 patients with hypertriglyceridemia, 49 had type III hyperlipoproteinemia, as diagnosed by the apoB algorithm and validated by ultracentrifugation. Plasma triglycerides were higher in the type III subjects: 4.16 mmol/L (3.35-6.08, 25th-75th percentile), but there was considerable overlap with the hypertriglyceridemic subjects 2.65 mmol/L (1.91-4.20, 25th-75th percentile) and the combined hyperlipidemic subjects 3.02 mmol/L (2.07-5.32, 25th-75th percentile). Similarly, total cholesterol was 4.79 mmol/L (4.31-5.58, 25th-75th percentile) for type III vs 5.5 mmol/L (4.64-5.78, 25th-75th percentile) and 7.02 mmol/L (6.39-7.96, 25th-75th percentile), respectively. By contrast, as identified by the apoB algorithm, the VLDL-C/TG, VLDL-C/VLDL-TG, VLDL-C/VLDL apoB, and VLDL apoB/LDL apoB ratios were all higher in type III than in the other hypertriglyceridemic dyslipoproteinemias with the exception of type V as diagnosed by the apoB algorithm., Conclusion: Cholesterol and triglycerides cannot reliably distinguish type III hyperlipoproteinemia from mixed hyperlipidemia. Adding apoB and applying the apoB algorithm makes reliable diagnosis possible and easy. However, unless apoB is introduced into routine clinical care, type III hyperlipoproteinemia will often not be recognized. Given the cardiovascular risk associated with type III and its responsiveness to treatment, this should not be acceptable., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size ( r = 0.31, P = 0.0002) and production rate ( r = 0.24, P = 0.008) but not the fractional catabolic rate ( r = -0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard β = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated ( r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR., (Copyright © 2018 Drouin-Chartier et al.)

The mechanisms underlying the oversecretion of apolipoprotein (apo)B-48-containing triglyceride-rich lipoproteins (TRL) in insulin-resistance (IR) states in humans remain to be fully understood. The objective of this study was to evaluate the association between the plasma levels of insulin and glucose and the intestinal expression of key genes involved in chylomicron metabolism in a large sample of nondiabetic men displaying various degrees of IR. Duodenal biopsies were obtained by gastroduodenoscopy in 127 men free of intestinal disease. Gene expression was measured using quantitative PCR in duodenal samples. Plasma insulin and glucose concentrations were measured in the fasting state. Postprandial TRL apoB-48 kinetics were measured using a primed-constant infusion of l-[5,5,5-D 3 ]leucine for 12 h in a subgroup of 75 subjects maintained in a constant fed state. Plasma insulin levels were negatively associated with intestinal expression of ACS1 (standard β = -0.20, P = 0.007), DGAT1 (β = -0.18, P = 0.001), DGAT2 (β = -0.20, P = 0.02), and MTP (β = -0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (β = 0.15, P = 0.04) independent of age, BMI, waist circumference, dietary intake, and duodenal expression of SREBP1c. Insulin levels, but not glucose concentrations, were positively correlated with postprandial TRL apoB-48 production rate ( r = 0.24, P = 0.04) and pool size ( r = 0.27, P = 0.03). In conclusion, plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism. These results suggest that alterations in intestinal lipoprotein metabolism associated with IR may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. NEW & NOTEWORTHY We demonstrate that plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism in men. For instance, intestinal expression of MTP is negatively associated with plasma insulin concentrations and positively associated with plasma glucose concentrations. Alterations in intestinal lipoprotein metabolism associated with insulin resistance may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency.

Context: Supplementation with high-dose docosahexaenoic acid (DHA) increases serum low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations more than high-dose eicosapentaenoic acid (EPA). The mechanisms underlying this difference are unknown., Objective: To examine the phenotypic change in LDL and mechanisms responsible for the differential LDL-C response to EPA and DHA supplementation in men and women at risk of cardiovascular disease., Design, Setting, Participants, and Intervention: In a double-blind, controlled, crossover study, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: phase 1, 2.7 g/d of EPA; phase 2, 2.7 g/d of DHA; and phase 3, 3 g/d of corn oil. All supplements were provided as three 1-g capsules for a total of 3 g/d. The 10-week treatment phases were separated by a 9-week washout period., Main Outcome Measure: In vivo kinetics of apolipoprotein (apo)B100-containing lipoproteins were assessed using primed-constant infusion of deuterated leucine at the end of each treatment in a subset of participants (n = 19)., Results: Compared with EPA, DHA increased LDL-C concentrations (+3.3%; P = 0.038) and mean LDL particle size (+0.7 Å; P < 0.001) and reduced the proportion of small LDL (-3.2%; P < 0.01). Both EPA and DHA decreased proprotein convertase subtilisin/kexin type 9 concentrations similarly (-18.2% vs -25.0%; P < 0.0001 vs control). Compared with EPA, DHA supplementation increased both the LDL apoB100 fractional catabolic rate (+11.4%; P = 0.008) and the production rate (+9.4%; P = 0.03)., Conclusions: The results of the present study have shown that supplementation with high-dose DHA increases LDL turnover and contributes to larger LDL particles compared with EPA.

Background and Aims: Maximizing the acute reduction of LDL-cholesterol (C) and lipoprotein (a) (Lp(a)) concentrations in patients with homozygous familial hypercholesterolemia (HoFH) is the main goal of lipoprotein apheresis (LA). The objective of this study was to examine how the pre-LA serum TG concentrations influence the efficacy of LA to acutely reduce LDL-C and Lp(a) concentrations in HoFH patients., Methods: Data from 1761 LA treatments of HoFH patients (n = 10) and compound heterozygous patients (n = 5) collected between 2008 and 2016 were analyzed. These data included the pre- and post-LA concentrations of LDL-C, TGs and Lp(a); volume of filtered plasma; type of LA system used (dextran sulfate adsorption (DSA) or heparin-induced extracorporeal LDL precipitation (HELP)); and interval between treatments., Results: A significant association between the pre-LA TG concentrations and acute LA-induced reduction in LDL-C, modified by the type of LA system used, was observed (p pre-LA TG quartile*LA system  = .04). Using the DSA system, the acute reduction of the LDL-C concentrations was attenuated by 3.9% when the pre-LA TG concentrations were >2.09 mmol/L vs. ≤0.93 mmol/L (highest vs. lowest quartiles: -59.4% vs. -63.3%, p = .007). Using the HELP system, no significant difference was observed in the reduction of LDL-C between the highest and the lowest quartiles of serum TGs (-65.8% vs. -66.4%, p = .9). No association was observed between pre-LA TG concentrations and acute LA-induced decrease in Lp(a) (p = .2)., Conclusions: The efficacy of LA is inversely associated with pre-LA TG concentrations in HoFH patients who used the DSA system instead of the HELP system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre- and post-LA. Concomitant reductions in LDL-C (median -73.8%, range: -55.9 to -82.0, P = .0001) and lipoprotein (a) concentrations (median -74.1%, range -65.6 to -84.1, P = .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P = .02), EGR3 (1.56-fold, P = .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P = .03). In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells., (© 2017 Wiley Periodicals, Inc.)

Background: The substitution of omega (ω)-6 (n-6) polyunsaturated fatty acids (PUFAs) for saturated fatty acids (SFAs) is advocated in cardiovascular disease prevention. The impact of this substitution on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains unknown., Objective: In men with dyslipidemia and IR, we evaluated the impact of substituting ω-6 PUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo) B-containing lipoproteins and on the intestinal expression of key genes involved in lipoprotein metabolism., Design: Dyslipidemic and IR men (n = 36) were recruited for this double-blind, randomized, crossover, controlled trial. Subjects consumed, in a random order, a fully controlled diet rich in SFAs (SFAs: 13.4% of energy; ω-6 PUFAs: 4.0%) and a fully controlled diet rich in ω-6 PUFAs (SFAs: 6.0%; ω-6 PUFAs: 11.3%) for periods of 4 wk, separated by a 4-wk washout period. At the end of each diet, the in vivo kinetics of apoB-containing lipoproteins were measured and the intestinal expression of key genes involved in lipoprotein metabolism was quantified in duodenal biopsies taken from each participant., Results: The substitution of ω-6 PUFAs for SFAs had no impact on TRL apoB-48 fractional catabolic rate (Δ = -3.8%, P = 0.7) and production rate (Δ = +1.2%, P = 0.9), although it downregulated the intestinal expression of the microsomal triglyceride transfer protein (Δ = -18.4%, P = 0.006) and apoB (Δ = -16.6%, P = 0.005). The substitution of ω-6 PUFAs for SFAs decreased the LDL apoB-100 pool size (Δ = -7.8%; P = 0.005). This difference was attributed to a reduction in the LDL apoB-100 production rate after the substitution of ω-6 PUFAs for SFAs (Δ = -10.0%; P = 0.003)., Conclusions: This study demonstrates that the substitution of dietary ω-6 PUFAs for SFAs decreases the production and number of LDL particles in men with dyslipidemia and IR. This trial was registered at clinicaltrials.gov as NCT01934543., (© 2018 American Society for Nutrition. All rights reserved.)

Background: In a simulated gastrointestinal environment, the cheese matrix modulates dairy fat digestion. However, to our knowledge, the impact of the cheese matrix on postprandial lipemia in humans has not yet been evaluated. Objective: In healthy subjects, we compared the impact of dairy fat provided from firm cheese, soft cream cheese, and butter on the postprandial response at 4 h and on the incremental area under the curve (iAUC) of plasma triglycerides. Design: Forty-three healthy subjects were recruited to this randomized, crossover, controlled trial. In random order at intervals of 14 d and after a 12-h fast, subjects ingested 33 g fat from a firm cheese (young cheddar), a soft cream cheese (cream cheese), or butter (control) incorporated into standardized meals that were matched for macronutrient content. Plasma concentrations of triglycerides were measured immediately before the meal and 2, 4, 6, and 8 h after the meal. Results: Cheddar cheese, cream cheese, and butter induced similar increases in triglyceride concentrations at 4 h (change from baseline: +59%, +59%, and +62%, respectively; P = 0.9). No difference in the triglyceride iAUC 0-8 h ( P -meal = 0.9) was observed between the 3 meals. However, at 2 h, the triglyceride response caused by the cream cheese (change from baseline: +44%) was significantly greater than that induced by butter (change from baseline: +24%; P = 0.002) and cheddar cheese (change from baseline: +16%; P = 0.0004). At 6 h, the triglyceride response induced by cream cheese was significantly attenuated compared with that induced by cheddar cheese (change from baseline: +14% compared with +42%; P = 0.0004). Conclusion: This study demonstrates that the cheese matrix modulates the impact of dairy fat on postprandial lipemia in healthy subjects. This trial was registered at clinicaltrials.gov as NCT02623790., (© 2017 American Society for Nutrition.)

Background: Previous studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH)., Methods: A total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state., Results: Plasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs., Controls: 194.5 ± 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs., Controls: 3.03 ± 2.07 μg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P = 0.5) and HeFH subjects (ρ = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001)., Conclusions: These data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels., Trial Registration: NCT02225340 .

The pro-inflammatory state and elevated plasma levels of post-prandial triglycerides (TG) are associated with increased cardiovascular disease risk. Recent studies suggested that the increase in the production rate of post-prandial lipoproteins observed in patients with insulin resistance (IR) may be caused, at least in part, by the dysregulation of intestinal insulin sensitivity triggered by inflammation., Objective: The objective of the present study was to evaluate the association between IR, plasma C-reactive protein (CRP) levels and the kinetics of TG-rich lipoprotein (TRL) containing apolipoprotein (apo) B-48 in a large sample of insulin sensitive (IS) and IR men., Methods: The in vivo kinetics of TRL apoB-48 were measured in 151 men following a primed-constant infusion of l-[5,5,5-D 3 ]leucine. IR subjects (n=91) were characterized by fasting TG levels ≥1.5mmol/L and an index of homeostasis model assessment of IR (HOMA-IR)≥2.5 or type 2 diabetes, while IS subjects (n=24) were characterized by an HOMA-IR index <2.5 and TG levels <1.5mmol/L., Results: IR subjects had higher TRL apoB-48 production rate (+202%; P<0.0001) and CRP levels (+51%; P=0.01) than IS subjects. TRL apoB-48 production rate and CRP levels were inversely correlated in IR subjects (r=-0.32; P=0.002). IR subjects with CRP levels above the median (2.20mg/L) had lower TRL apoB-48 production rate than IR subjects with CRP levels below the median (Δ=-24%; P<0.05)., Conclusion: Our results confirm that IR is associated with increased TRL apoB-48 secretion and suggest that a higher inflammatory status is associated with decreased TRL apoB-48 secretion among IR subjects., (Copyright © 2016. Published by Elsevier Inc.)

Aim: To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)-mediated uptake of lipoproteins., Methods: A total of 25 men with dyslipidaemia and IR were recruited to participate in this double-blind, randomized, crossover, placebo-controlled trial. Participants received 10 mg/day ezetimibe or placebo for periods of 12 weeks each. Intestinal gene expression was measured by quantitative PCR in duodenal biopsy samples collected by gastroduodenoscopy at the end of each treatment., Results: A total of 20 participants completed the protocol. Treatment with ezetimibe significantly increased intestinal LDLR (+16.2%; P = .01), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR; +14.0%; P = .04) and acetyl-Coenzyme A acetyltransferase 2 (ACAT-2) mRNA expression (+12.5%; P = .03). Changes in sterol regulatory element-binding transcription factor 2 (SREBP-2) expression were significantly correlated with changes in HMG-CoAR (r = 0.55; P < .05), ACAT-2 (r = 0.69; P < .001) and proprotein convertase substilisin/kexin type 9 (PCSK9) expression (r = 0.45; P < .05)., Conclusions: These results show that inhibition of intestinal cholesterol absorption by ezetimibe increases expression of the LDLR gene, supporting the concept that increased LDL clearance with ezetimibe treatment occurs not only in the liver but also in the small intestine., (© 2016 John Wiley & Sons Ltd.)

Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL-C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P < 0.0001), and TNF-α (-23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (-45.3% vs. -63.4%; P = 0.31), lipoprotein (a) (-70.6% vs. -65.0%; P = 0.30), E-selectin (-16.6% vs. -18.3%; P = 0.65), ICAM-1 (-4.0 vs. 5.6%; P = 0.56), and VCAM-1 (8.3% vs. -1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (-63.1% vs. -58.3%; P = 0.04), HDL-C (-20.6% vs. -6.5%; P = 0.003), and PCSK9 (-63.4% vs. -28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359-367, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been proposed to modulate plasma lipids, lipoprotein metabolism, and inflammatory state and to reduce triglyceride (TG) concentrations. The present double-blind, randomized, placebo-controlled, crossover study investigated the effects of n-3 PUFA supplementation at 3 g/d for 8 weeks on the intravascular kinetics of intestinally derived apolipoprotein (apo) B-48-containing lipoproteins in 10 men with type 2 diabetes. In vivo kinetics of the TG-rich lipoprotein (TRL) apoB-48 and VLDL apoB-100 were assessed using a primed-constant infusion of L-[5,5,5-D3] leucine for 12 hours in a fed state. Compared with the placebo, n-3 PUFA supplementation significantly reduced fasting TG concentrations by -9.7% (P = 0.05) but also significantly increased plasma levels of cholesterol (C) (+6.0%, P = 0.05), LDL-C (+12.2%, P = 0.04), and HDL-C (+8.4, P = 0.007). n-3 PUFA supplementation had no significant impact on postprandial TRL apoB-48 and VLDL apoB-100 levels or on the production or catabolic rates of these lipoproteins. These data indicate that 8-week supplementation with n-3 PUFAs in men with type 2 diabetes has no beneficial effect on TRL apoB-48 and VLDL apoB-100 levels or kinetics.

Unlabelled: Autosomal dominant familial hypercholesterolemia (FH) is caused by genetic mutations in the LDL receptor (LDLR), its ligand apolipoprotein (apo) B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Although PCSK9 levels have been shown to correlate with LDL-cholesterol (LDL-C) levels in FH, the extent to which PCSK9 levels modulate the phenotypic severity of this disease independent of LDLR genotype remains to be clarified., Objective: To assess the relationship between LDLR genotype and the plasma levels of PCSK9, LDL-C, and lipoprotein (a) (Lp(a)) in a large cohort of genetically defined FH heterozygotes (HeFH)., Methods: A total of 292 HeFH carrying one of the nine French-Canadian mutations in the LDLR gene were recruited. The cohort included 226 carriers of a negative-receptor (NR) mutation and 66 carriers of a defective-receptor (DR) LDLR gene mutation. Fifty-six control subjects, who were matched with the HeFH subjects based on gender and body mass index, were also recruited., Results: PCSK9 levels were higher in the HeFH group than in the control group (317.9±107.1 ng/mL vs. 203.3±59.8 ng/mL; P<0.0001). The strength of the association between PCSK9 and LDL-C levels was similar among controls (r=0.37; P=0.005) and HeFH (r=0.31; P<0.0001). Furthermore, a multiple linear regression analysis revealed that the positive correlation between PCSK9 and LDL-C levels remained significant after adjusting for LDLR genotype in the HeFH group., Conclusion: These results suggested that the contribution of PCSK9 levels to the phenotypic severity in FH heterozygotes is independent of LDLR genotype., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To investigate the effects of sitagliptin therapy on the kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo)B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes., Methods: Twenty-two subjects with type 2 diabetes were recruited in this double-blind crossover study, during which the subjects received sitagliptin (100 mg/day) or placebo for a 6-week period each. At the end of each phase of treatment, the in vivo kinetics of the different apolipoproteins were assessed using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h, with the participants in a constantly fed state., Results: Sitagliptin therapy significantly reduced fasting plasma triglyceride (-15.4%, p = 0.03), apoB-48 (-16.3%, p = 0.03) and free fatty acid concentrations (-9.5%, p = 0.04), as well as plasma HbA1c (placebo: 7.0% ± 0.8 vs. sitagliptin: 6.6% ± 0.7, p < 0.0001) and plasma glucose levels (-13.5%, p = 0.001), without any significant effect on insulin levels. Kinetic results showed that treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (p = 0.03), paralleled by a reduction in the production rate of these particles (-16.0%, p = 0.03). The VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, p = 0.03), mainly because of a reduction in the hepatic secretion of these lipoproteins, although this difference did not reach statistical significance (-9.2%, p = 0.06)., Conclusions: Treatment with sitagliptin for 6 weeks reduced triglyceride-rich apoB-containing lipoprotein levels by reducing the synthesis of these particles., (© 2014 John Wiley & Sons Ltd.)

Unlabelled: Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized., Objective: The objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes., Methods and Results: Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m²) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A₂ (sPLA₂) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E-selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels., Conclusions: Treatment with sitagliptin for 6 weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Several studies have presented evidence suggesting that dairy consumption has beneficial effects on blood pressure (BP) in healthy subjects; however, only a few studies have examined this possibility in patients with established essential hypertension using ambulatory blood pressure monitoring. The objective of this study was to investigate how consuming dairy products impacts mean daytime systolic and diastolic BP in men and women with mild to moderate essential hypertension., Methods: Eighty-nine men and women with systolic BP ≥ 135 mm Hg and ≤ 160 mm Hg and diastolic BP ≤ 110 mm Hg were enrolled in this single-blind, randomized, cross-over, controlled study. Participants had to incorporate three daily servings of dairy products or control products equivalent in macronutrients and sodium during four-week treatment phases. Twenty-four hour ambulatory BP and endothelial function were assessed at screening and at the end of each dietary phase., Results: The consumption of three daily servings of dairy products led to a significant reduction in mean daytime ambulatory systolic BP (-2 mm Hg; P = 0.05) in men compared with readings after the control phase. In women, dairy consumption had no effect on ambulatory systolic BP. Moreover, endothelial function was significantly improved by dairy consumption in the whole cohort., Conclusion: These data indicate that the consumption of three daily servings of dairy products have beneficial effects on daytime systolic ambulatory BP compared to a heart-healthy, dairy-free, diet in men with mild to moderate essential hypertension., Trial Registration: This trial is registered at clinicaltrials.gov as NCT01776216.

Objectives: This study tests the validity of the Hattori formula to calculate LDL apoB based on plasma lipids and total apoB., Methods: In 2178 patients in a tertiary care lipid clinic, LDL apoB calculated as suggested by Hattori et al. was compared to directly measured LDL apoB isolated by ultracentrifugation., Results: In subjects with plasma triglycerides ≥ 3.0 mmol/L, there was considerable discordance between calculated and measured LDL apoB. In all others, the relation between measured LDL apoB and calculated LDL apoB could be expressed as LDL apoB = 0.86 [total apoB - 0.9 TC (mg/dL) + 0.09 HDL-C (mg/dL) - 0.08 TG (mg/dL)] - 7.0 (r > 0.91; P < 0.0001)., Conclusions: Our results indicate that LDL apoB can be calculated with reasonable accuracy when triglycerides are <3.0 mmol/L. However, the calculation suggested by Hattori et al. should be corrected based on the regression demonstrated between calculated and measured LDL apoB in subjects with a plasma triglyceride <3.0 mmol/L., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the effect of a Mediterranean diet (MedDiet) with and without weight loss (WL) on apolipoprotein B100 (apoB100) metabolism in men with metabolic syndrome., Approach and Results: The diet of 19 men with metabolic syndrome (age, 24-62 years) was first standardized to a North American isoenergetic control diet for 5 weeks, followed by an isoenergetic MedDiet for an additional 5 weeks under full-feeding conditions (MedDiet-WL). Participants next underwent a 20-week supervised WL program under free-living conditions (-10.2 ± 2.9% body weight; P<0.01) and finally consumed the MedDiet (5 weeks) under weight-stabilizing feeding conditions (MedDiet+WL). In vivo kinetic of apoB100 was assessed in the fasted state at the end of the 3 controlled diets using a bolus of D3-leucine. Compared with the control diet, MedDiet-WL reduced low-density lipoprotein (LDL)-apoB100 pool size (-14.2%, P<0.01) primarily through an increase in LDL-apoB100 fractional catabolic rate (+30.4%, P=0.02) and increased LDL particle size (P<0.01) but had no effect on very-LDL (VLDL)-apoB100 pool size or triglyceride concentrations, despite a significant increase in VLDL-apoB100 fractional catabolic rate (+25.6%; P=0.03). MedDiet+WL had no further effect on LDL-apoB100 pool size and fractional catabolic rate but further increased LDL particle size and reduced VLDL-apoB100 pool size versus the control diet primarily through an increase in VLDL-apoB100 fractional catabolic rate (+30.7%; P<0.01)., Conclusions: Consumption of MedDiet increases LDL size and reduces LDL-apoB100 concentrations primarily by increasing the catabolism of LDL even in the absence of WL in men with metabolic syndrome. MedDiet seems to have a trivial effect on VLDL concentrations and kinetics unless accompanied by significant WL., Clinical Trial Registration -Url: http://www.clinicaltrials.gov. Unique identifier: NCT00988650.

Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D₃]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism was assessed by performing real-time PCR quantification and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% (P < 0.0001) and 87% (P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4α, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism.

Background: Medium-chain triglyceride (MCT) supplements are used by clinicians to treat patients with severe hypertriglyceridemia who are at risk of pancreatitis. However, the potential mechanisms underlying the effects of MCT on triglyceride-rich lipoprotein (TRL) metabolism have not yet been thoroughly examined in humans., Objective: This double-blind randomized crossover study compared the impact of 4 wk of supplementation with 20 g MCT oil/d or 20 g corn oil/d on the kinetics of apolipoprotein (apo) B-48-containing TRLs and apo B-100-containing very-low-density lipoprotein (VLDL), as well as on the expression of key intestinal genes involved in lipid metabolism in 28 obese, insulin-resistant men., Design: The in vivo kinetics of TRL apo B-48 and VLDL apo B-100 were assessed by using a primed-constant infusion of l-[5,5,5-d3]leucine for 12 h in the fed state. Real-time polymerase chain reaction quantification was performed on duodenal biopsy samples taken at the end of each phase of supplementation., Results: Compared with corn oil, MCT supplements had no significant effect on plasma lipoprotein profile or TRL apo B-48 and VLDL apo B-100 kinetics. Positive correlations were observed between the intestinal expression of several key genes involved in lipoprotein metabolism in a subgroup of participants (n = 16) after MCT supplementation. However, there was no difference between MCT and the corn oil control supplement in the intestinal messenger RNA expression levels of these key genes., Conclusion: These data indicate that short-term supplementation with MCT has a neutral effect on TRL apo B-48 and VLDL apo B-100 kinetics and on the intestinal expression of genes involved in lipid and fatty acid metabolism in men with insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT01806142.

Background: The extent to which long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) from fish oil such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert their anti-inflammatory effects by down-regulating intestinal inflammation in humans is unknown. We investigated the impact of LCn-3PUFA supplementation on inflammatory gene expression in the duodenum of obese patients with type 2 diabetes., Findings: This placebo-controlled randomized crossover study included 12 men with type 2 diabetes. After a 4-week run-in period, patients received in a random sequence 5 g/d of fish oil (providing 3 g of EPA + DHA) and a placebo (corn and soybean oil) for 8 weeks each. The two treatment phases were separated by a 12-week washout period. Gene expression was assessed by real-time polymerase chain reaction in duodenal biopsy samples obtained in the fasted state at the end of each treatment phase. Intestinal mRNA expression levels of interleukin (IL)-6 and tumor-necrosis factor (TNF)-α were hardly detectable after either treatment (<100 copies/105 copies of the reference gene ATP5o). Intestinal mRNA expression of IL-18 and of the transcription factor signal transducer and activator of transcription 3 (STAT3) was higher (>5000 copies/105 copies ATP5o) but still relatively low. EPA + DHA supplementation had no impact on any of these levels (all P ≥ 0.73)., Conclusions: These data suggest that duodenal cells gene expression of pro-inflammatory cytokines is low in patients with type 2 diabetes and not affected by EPA + DHA supplementation. Further studies are warranted to determine if inflammatory gene expression in other tissues surrounding the intestine is modulated by EPA + DHA supplementation., Trial Registration: ClinicalTrials.gov ID: NCT01449773.

Background: The modulation of cholesterol and fatty acid homeostasis by dietary fatty acids is thought to be mediated by changes in the expression of key intestinal genes involved in lipoprotein metabolism. However, the short-term effect of dietary fat intake on the expression of these genes has not been fully investigated in humans., Objective: To test whether short-term changes in dietary fatty acid intake affect the expression of key intestinal genes involved in lipoprotein metabolism, we conducted a randomized, double-blind, crossover study in 12 nonobese, healthy men with normal plasma lipid profiles., Design: Participants were subjected to the following 2 intensive 3-d dietary interventions under isocaloric conditions: 1) a high-fat diet (37% of energy from fat and 50% of energy from carbohydrates) and 2) a low-fat diet (25% of energy from fat and 62% of energy from carbohydrates). Expressions of key genes involved in lipoprotein metabolism were compared by using real-time polymerase chain reaction quantification on duodenal biopsy specimens obtained in a fasting state after each diet., Results: After the 3-d high-fat diet, plasma cholesterol, LDL cholesterol, and HDL cholesterol concentrations were significantly higher than concentrations observed after the low-fat diet was consumed. The high-fat diet also resulted in significant increases in the intestinal messenger RNA expression of several key genes involved in lipoprotein metabolism. Plasma triglycerides and apolipoprotein B-48 concentrations were significantly lower after the high-fat diet than after the low-fat diet., Conclusion: These findings suggest that short-term exposure to a high-fat diet upregulates the expression of key genes involved in lipid and lipoprotein metabolism at the enterocyte level. This trial was registered at clinicaltrials.gov as NCT01806441.

High-fat, low-carbohydrate diets have been shown to raise plasma cholesterol levels, an effect associated with the formation of large low-density lipoprotein (LDL) particles. However, the impact of dietary intervention on time-course changes in LDL particle size has not been investigated. To test whether a short-term dietary intervention affects LDL particle size, we conducted a randomized, double-blind, crossover study using an intensive dietary modification in 12 nonobese healthy men with normal plasma lipid profile. Participants were subjected to 2 isocaloric 3-day diets: high-fat diet (37% energy from fat and 50% from carbohydrates) and low-fat diet (25% energy from fat and 62% from carbohydrates). Plasma lipid levels and LDL particle size were assessed on fasting blood samples after 3 days of feeding on each diet. The LDL particles were characterized by polyacrylamide gradient gel electrophoresis. Compared with the low-fat diet, plasma cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol were significantly increased (4.45 vs 4.78 mmol/L, P = .04; 2.48 vs 2.90 mmol/L, P = .005; and 1.29 vs 1.41 mmol/L, P = .005, respectively) following the 3-day high-fat diet. Plasma triglycerides and fasting apolipoprotein B-48 levels were significantly decreased after the high-fat diet compared with the low-fat diet (1.48 vs 1.01 mmol/L, P = .0003 and 9.6 vs 5.5 mg/L, P = .008, respectively). The high-fat diet was also associated with a significant increase in LDL particle size (255.0 vs 255.9 Å;P = .01) and a significant decrease in the proportion of small LDL particle (<255.0 Å) (50.7% vs 44.6%, P = .01). As compared with a low-fat diet, the cholesterol-raising effect of a high-fat diet is associated with the formation of large LDL particles after only 3 days of feeding., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: Recent studies indicate that type 2 diabetes is associated with an increased secretion of both hepatic and intestinal lipoproteins, leading to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins. Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 that has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes presumably through incretin hormone-mediated improvements in islet function. The objective of the present study is to examine the effects of treatment with sitagliptin on postprandial lipid and incretin hormone levels as well as glucose homeostasis in patients with type 2 diabetes., Methods: Thirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1 ± 6.4 years and a body mass index of 30.7 ± 4.9 kg/m(2) ) were recruited in this double-blind cross-over study using sitagliptin 100 mg/day or placebo for a 6-week period each, with a 4-week washout period between the two phases. At the end of each phase of treatment, patients underwent an oral lipid tolerance test providing 35 g of fat per m(2) of body surface area and blood samples were taken over an 8-h period., Results: Sitagliptin therapy significantly decreased the postprandial area under the curves (AUCs) for plasma apolipoprotein (apo)B (-5.1%, p = 0.002), apoB-48 (-7.8%, p = 0.03), TG (-9.4%, p = 0.006), very low-density lipoprotein (VLDL)-cholesterol (-9.3%, p = 0.001), free fatty acids (FFAs) (-7.6%, p = 0.005) and glucose (-9.7%, p < 0.0001). Furthermore, the postprandial AUCs for plasma intact glucagon-like peptide-1 (+67.8%, p < 0.0001) and glucose-dependent insulinotropic polypeptide (+67.3%, p < 0.0001) were significantly increased following treatment with sitagliptin, whereas the AUC for plasma glucagon was reduced by -9.7% (p = 0.001) with no significant changes in the AUCs for plasma insulin and C-peptide. Sitagliptin therapy also improved homeostasis model assessment (HOMA) index for insulin resistance (-14.6%, p = 0.01) and β-cell function (+32.3%, p = 0.007)., Conclusions: Treatment with sitagliptin for 6 weeks reduced postprandial plasma levels of TG-rich lipoproteins of both intestinal and hepatic origin, most likely by increasing incretin hormone levels, reducing circulating plasma FFA concentrations and improving insulin sensitivity and β-cell function., (© 2011 Blackwell Publishing Ltd.)

Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.

Objectives: To assess the relationship between commonly used lipid indices and LDL peak particle diameter (LDL-PPD) in a large cohort of 1955 subjects., Design and Methods: Four statistical methods were used for comparison: correlation, concordance analysis, kappa statistics and receiver operating characteristic curve (ROC) analysis., Results: Plasma triglyceride (TG) levels, TG/HDL-C, LDL-C/apoB, total cholesterol (TC)/TG, LDL-C/TG, and TG/apoB ratios were best correlated with LDL-PPD but none of these ratios accounted for more than 45% of the variation in LDL-PPD. Moreover, across the range of the lipid indices and LDL-PPD quintiles, just under 40% of the values were concordant, with kappas varying between 0.20 and 0.25. Finally, plasma TG levels and the lipid ratios yielded areas under the ROC curve between 0.78 and 0.80., Conclusions: The present study does not support the concept that plasma TG levels and the commonly used lipid indices may be considered as adequate surrogates for the small dense LDL phenotype. Our data also indicate that various lipid indices are not superior to plasma TG levels alone as a clinical tool for prediction of the small dense LDL phenotype., (Copyright 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (-43.0%), LDL-C (-53.6%), and triglycerides (-44.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (-48.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (-38.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r = 0.85; P < 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.

Type 2 diabetes mellitus is associated with elevated plasma triglyceride levels, low high-density lipoprotein cholesterol, and a high incidence of cardiovascular disease. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates are frequently used in the treatment of diabetic dyslipidemia, but their specific impact on the inflammation processes involved in atherosclerosis remains to be fully characterized. The objective of this 2-group parallel study was to investigate the differential effects of a 6-week treatment with either atorvastatin 20 mg/d alone (n = 19) or micronized fenofibrate 200 mg/d alone (n = 19) on inflammation, cell adhesion, and oxidation markers in type 2 diabetes mellitus subjects with marked hypertriglyceridemia. In addition to the expected changes in lipid levels, atorvastatin decreased plasma levels of C-reactive protein (-26.9%, P = .004), soluble intercellular adhesion molecule 1 (-5.4%, P = .03), soluble vascular cell adhesion molecule 1 (-4.4%, P = .008), sE-selectin (-5.7%, P = .02), matrix metalloproteinase 9 (-39.6%, P = .04), secretory phospholipase A(2) (sPLA(2)) (-14.8%, P = .04), and oxidized low-density lipoprotein (-38.4%, P < .0001). On the other hand, fenofibrate had no significant effect on C-reactive protein levels and was associated with reduced plasma levels of sE-selectin only (-6.0%, P = .04) and increased plasma levels of sPLA(2) (+22.5%, P = .004). These results suggest that atorvastatin was potent to reduce inflammation, oxidation, and monocyte adhesion in type 2 diabetes mellitus subjects with marked hypertriglyceridemia, whereas fenofibrate decreased sE-selectin levels only and was associated with an elevation of sPLA(2) levels.

The specific impact of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D(3)]-l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.

Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n = 11) and nondiabetic controls (n = 13) using a primed-constant infusion of l-[5,5,5-D(3)]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these subfractions.

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH=87.3+/-5.2 Angstroms versus controls=91.6+/-4.9 Angstroms, P<0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.

Objectives: To examine the relationship between plasma triglycerides (TG) to HDL-cholesterol (HDL-C) or HDL apo A-I., Design and Methods: Bivariate and multiple linear regression analyses in a large cohort of 1886 subjects., Results: Higher plasma TG levels were associated with lower concentrations of both HDL-C and HDL-apo A-I. However, the HDL-C/HDL-apo A-I ratio was inversely correlated with plasma TG indicating that the overall composition of the HDL changed as plasma TG changed. Plasma TG levels contributed to 15.9% of the variance of the HDL-C/HDL-apo A-I ratio, whereas gender, HDL-TG, LDL-TG, body mass index and plasma apo B levels represented between 0.15% and 2.21% of this variance., Conclusions: These results indicate that increasing levels of plasma TG result in greater reduction in HDL-C levels than in HDL-apo A-I and this might explain, at least in part, the differences that have been observed in the magnitude of the association of HDL-C versus HDL-apo A-I with the risk of cardiovascular disease.

Dysbetalipoproteinemia (dysb) and familial hypercholesterolemia (FH) are two genetic disorders giving rise to severe disturbances of lipid homeostasis and premature atherosclerosis. The co-occurrence of both metabolic abnormalities is very rare and is estimated to affect 1 individual per 2,500,000 in the general population. However, the relative contribution of these two dyslipidemias to the combined lipoprotein phenotype is unknown. The two objectives of this study were (1) to compare the in vivo kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo) B48, VLDL, IDL and LDL apo B100 as well as plasma apo A-l labelled with a stable isotope (l-(5,5,5-D3) leucine) in two subjects presenting both heterozygous FH and dysbetalipoproteinemia (FH+/dysb+), in six FH heterozygotes and in five normolipidemic controls, and (2) to examine the impact of a 6-week treatment with micronized fenofibrate 200 mg/d on apolipoprotein kinetics in FH+/dysb+. As compared with FH heterozygotes and controls, the two FH+/dysb+ subjects showed elevated TRL apo B48 and VLDL, IDL apo B100 pool sizes (PS) mainly due to lower fractional catabolic rates (FCR). Moreover, as compared with FH heterozygotes, FH+/dysb+ subjects presented lower LDL apo B100 PS due to a higher FCR. Pool size, FCR and production rate (PR) of apo A-l were higher in FH+/dysb+ subjects than in FH heterozygotes. In FH+/dysb+ subjects, fenofibrate treatment was associated with a decreased TRL apo B48 PS (-52 and -61%), VLDL apo B100 (-61 and -63%) and IDL apo B100 (-37 and -16%) and an increased FCR of TRL apo B48 (10 and 67%), VLDL apo B100 (123 and 57%) and IDL apo B100 (29 and 10%). Fenofibrate also increased LDL apo B100 PS (3 and 57%) due to an increase in PR (80 and 26%) but had divergent effects on LDL apo B100 FCR. These results indicate that the coexistence of dysbetalipoproteinemia and heterozygous FH results in a mixed lipoprotein phenotype that is intermediate between the two pure phenotypes and that fenofibrate treatment partially reverses lipoprotein abnormalities, mostly through changes in PR and FCR of apo B48- and B100-containing lipoproteins.

Objective: To examine the impact of ezetimibe, a selective inhibitor of intestinal cholesterol absorption, on the in vivo kinetics of apolipoproteins (apo) B-48 and B-100 in humans., Methods and Results: Kinetics of triglyceride-rich lipoprotein (TRL) apoB-48 and very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100 labeled with a stable isotope were assessed at baseline and at the end of 8 weeks of treatment with 10 mg/d of ezetimibe in 8 men with moderate primary hypercholesterolemia. Data were fit to a multicompartmental model using SAAMII to calculate fractional catabolic rate (FCR) and production rate (PR). Ezetimibe significantly decreased total and LDL cholesterol concentrations by -14.5% and -22.0% (P=0.004), respectively, with no significant change in plasma triglyceride and high-density lipoprotein (HDL) cholesterol levels. Ezetimibe had no significant effect on TRL apoB-48 kinetics and pool size (PS). However, VLDL and IDL apoB-100 FCRs were significantly increased (+31.2%, P=0.02 and +20.8%, P=0.04, respectively) with a concomitant elevation of VLDL apoB-100 PR (+20.9%, P=0.04). Furthermore, LDL apoB-100 PS was significantly reduced by -23.2% (P=0.004), caused by a significant increase in FCR of this lipoprotein fraction (+24.0%, P=0.04)., Conclusions: These results indicate that reduction of plasma LDL cholesterol concentration after treatment with ezetimibe is associated with an increase in FCR of apoB-100-containing lipoproteins.

Small, dense LDL particles have been associated with an increased risk of coronary artery disease. In order to assess the potential contribution of the genotype of the LDL receptor to LDL particle size heterogeneity in familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of LDL particles in a large cohort of FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. LDL particles were characterized by polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. LDL-peak particle diameter (LDL-PPD), representing the most abundant LDL particle subpopulation, was significantly smaller in FH heterozygotes carrying a negative-receptor mutation than in subjects carrying a defective-receptor mutation (negative-receptor = 257.3 +/- 4.1 A versus defective-receptor = 259.0 +/- 4.3 A, p = 0.0006). No significant difference in plasma CETP concentrations was found between these two genotypic groups. Moreover, compared with controls having low triglyceride levels, negative-receptor subjects with high triglyceride levels had a relative risk of 19.6 (p < 0.0001) of having small, dense LDL particles while this risk was not significantly increased among defective-receptor subjects. Multivariate analysis showed that the LDL receptor status accounted for 5.7% of the variance in the LDL-PPD after adjustment for covariates. These results suggest that the genotype of the mutant LDL receptor allele was independently associated with variations in LDL-PPD and could partly explain why negative-receptor FH heterozygotes may be at greater risk of cardiovascular disease than defective-receptor FH subjects.

Lipoprotein data and apolipoprotein (apo) E genotype from 1302 participants, covering a wide range of total plasma cholesterol levels, were used to examine the impact of apo E genotype on the estimation of low-density lipoprotein cholesterol (LDL-C0 concentrations by the Friedewald formula using high-density lipoprotein cholesterol and triglyceride (TG) concentrations as compared with the beta -quantification reference procedure. The results showed that participants with apo E2/E2 genotype had significantly higher very low-density lipoprotein cholesterol (VLDL-C) concentrations and VLDL-C/TG ratio as well as lower LDL-C concentrations than participants with other apo E genotypes. Heterozygous carriers of the epsilon 2 allele had significantly higher VLDL-C than participants with apo E3/E3 and E4/E3 genotypes. The mean absolute error and the mean percentage of bias in calculated LDL-C according to all apo E genotypes, except E2/E2 genotype, were less than 0.16 mmol/L and 4.4%, respectively. Indeed, the mean error and the mean percentage of bias associated with the LDL-C calculated by the Friedewald formula in the apo E2/E2 group were 0.93 mmol/L and 40.6%, respectively. However, participants with the apo E2/E2 genotype and a type III phenotype showed a mean error and a mean percentage of bias reaching 1.53 mmol/L and 63.5%, respectively, whereas E2/E2 participants with a non-type III phenotype had a mean error and a mean percentage of bias of 0.18 mmol/L and 11.0%, respectively. Moreover, 41.9% to 57.1% of the participants had an absolute bias higher than 5% according to the apo E genotype, except for the apo E2/E2 genotypic group where 88.6% of the participants had an absolute bias higher than 5%. Stepwise multiple linear regression analyses revealed that the apo E genotype contributed to 39.0% of the VLDL-C/TG ratio variance, whereas sex, age, and high-density lipoprotein cholesterol explained between 0.5% and 3.2% of the variance. These results indicate that the apo E genotype exerts a significant influence on the estimation of LDL-C concentrations by the Friedewald formula as compared with the beta-quantification.

Lipoprotein data from 9477 subjects, covering a wide range of total plasma cholesterol levels, were used to examine the validity of the Friedewald formula for estimating plasma concentrations of low-density lipoprotein cholesterol (LDL-C) using high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. Values of LDL-C obtained from the Friedewald formula were compared with values of LDL-C derived from preparative ultracentrifugation used as a reference method. We found that the bias associated with the Friedewald formula was not related to plasma LDL-C levels and was smaller than -4.0% even for plasma LDL-C values <3.0 mmol/l. Moreover, in the subgroup of individuals with plasma TG levels < or =4.5 mmol/l, the Friedewald formula underestimated LDL-C levels with a bias between -3.1% and -1.9% according to TG quartiles. Interestingly, the Friedewald formula showed no significant bias in patients with plasma TG levels between 4.51 and 8.82 mmol/l, suggesting that the calculated LDL-C are reliable and could be clinically useful in patients with plasma TG levels higher than 4.5 mmol/l which is the reference cut-point value used by most clinical laboratories. Finally, multiple regression analyses showed that the very low-density lipoprotein cholesterol (VLDL-C)/TG ratio represented nearly 63% (P < 0.0001) of the variance of the bias associated with the Friedewald formula. We concluded that the Friedewald formula may be reliable at low LDL-C levels and at TG levels up to 9 mmol/l but may be used with caution when the VLDL-C/TG ratio is high as observed in patients with type III dysbetalipoproteinemia.

Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 +/- 4.8 vs. 259.2 +/- 4.1 A; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = -0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis.

Early radiokinetic studies revealed that the classical metabolic defect in patients with familial hypercholesterolemia (FH) is hypocatabolism of LDL due to decreased LDL receptor activity. However, recent studies have suggested that hepatic oversecretion of apolipoprotein B-100 (apoB-100)-containing lipoproteins could also contribute to the markedly elevated plasma concentrations of LDL-cholesterol found in FH. The aim of this study was to examine the kinetics of apoB-100 labeled with a stable isotope (l-[5,5,5-D(3)] leucine) in five normolipidemic controls and in seven well-characterized FH subjects that included six FH heterozygotes and one FH homozygote carrying the same null LDL receptor gene mutation. As compared with controls, the VLDL apoB-100 production rate was increased by 50% in the FH heterozygotes and by 109% in the FH homozygote. Furthermore, FH subjects had significantly higher LDL apoB-100 pool size and lower LDL apoB-100 fractional catabolic rate than controls. These results indicate that the elevation of plasma LDL-cholesterol found in FH is attributable to both decreased clearance of LDL and increased hepatic production of apoB-100-containing lipoproteins.