Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men.

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/m2, 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.

Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance.

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 ß = +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.

Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism.

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-D3]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 ß = -0.20, P = 0.007), DGAT1 (ß = -0.18, P = 0.001), DGAT2 (ß = -0.20, P = 0.02), and MTP (ß = -0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (ß = 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.

Impact of lipoprotein apheresis with dextran-sulfate adsorption on the expression of genes involved in cardiovascular health in the blood of patients with homozygous familial hypercholesterolemia.

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.

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels.

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 .

Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance.

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.

Comparison of two low-density lipoprotein apheresis systems in patients with homozygous familial hypercholesterolemia.

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.

Effect of Mediterranean diet with and without weight loss on apolipoprotein B100 metabolism in men with metabolic syndrome.

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.

Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance.

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.

Impact of dairy consumption on essential hypertension: a clinical study.

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.

Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases low-density lipoprotein apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial.

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.

Eicosapentaenoic and docosahexaenoic acid supplementation and inflammatory gene expression in the duodenum of obese patients with type 2 diabetes.

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.

Validation of an automated self-administered 24-hour dietary recall web application against urinary recovery biomarkers in a sample of French-speaking adults of the province of Québec, Canada.

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.

Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men.

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.

Correlates of Coronary Artery Calcification Prevalence and Severity in Patients With Heterozygous Familial Hypercholesterolemia.

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.

CONTEXTE: Les déterminants de la prévalence et de la sévérité de la calcification des artères coronaires (CAC) dans l'hypercholestérolémie familiale hétérozygote (HFHe) demeurent peu étudiés. L'objectif de cette étude transversale était d'identifier les corrélats de la CAC chez des patients atteints d'HFHe. MÉTHODOLOGIE: Un score calcique coronarien (SCC) a été calculé par un examen de tomodensitométrie sans contraste chez des femmes (n = 68) et des hommes (n = 78) avec HFHe génétiquement définie. Nous avons classé la prévalence et la gravité de la CAC en trois catégories : SCC = 0 unité d'Agatston (UA), SCC = 1 à 100 UA et SCC > 100 UA. Des renseignements ont été recueillis sur des corrélats potentiels de la CAC, dont les antécédents médicaux familiaux et personnels, les facteurs de risque cardiovasculaire, les médicaments hypolipidémiants et les habitudes de vie. RÉSULTATS: Au total, 95 patients présentaient une CAC. Les corrélats indépendants de la prévalence et de la gravité de la CAC comprenaient l'âge (rapport de cotes [RC] par tranche de 10 ans : 5,06; intervalle de confiance [IC] à 95 % : 3,19 à 7,93; p < 0,0001), des antécédents familiaux de maladie cardiovasculaire précoce (RC : 3,88; IC à 95 % : 1,71 à 8,81; p = 0,001), le sexe masculin (RC : 3,40; IC à 95 % : 1,49 à 7,78; p = 0,004), l'emploi de statines (RC : 15,5; IC à 95 % : 1,89 à 126; p = 0,01), la qualité du régime alimentaire évaluée selon le score AHEI (Alternative Healthy Eating Index) (RC par écart-type : 0,59; IC à 95 % : 0,39 à 0,90; p = 0,01), le tabagisme (RC : 3,06; IC à 95 % : 1,20 à 7,81; p = 0,02), le génotype récepteur-négatif (RC : 3,17; IC à 95 % : 1,16 à 8,66; p = 0,02) et le score lipoprotéine(a)-année (RC par écart-type du score-année transformé en logarithme : 1,53; IC à 95 % : 0,99 à 2,36; p = 0,05). CONCLUSIONS: Chez les personnes atteintes d'HFHe, l'âge, les antécédents familiaux de maladie cardiovasculaire précoce, le sexe, l'emploi de statines, la qualité du régime alimentaire, le statut de tabagisme, le génotype du LDLR et les concentrations de lipoprotéine(a) ont été associés de façon indépendante à la prévalence et à la gravité de la CAC.

Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations.

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 UHPLC­MS 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.

Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia.

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.

Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia.

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.

Differential effect of atorvastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus.

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.