Postprandial Lipoprotein Metabolism Research Articles

Chinese migrants exhibit impaired postprandial lipaemia compared to Caucasian counterparts following both high fat and high carbohydrate test meals.

People of Chinese ethnicity develop type 2 diabetes mellitus (T2DM) at a younger age and lower body mass index (BMI) than their Caucasian counterparts. Furthermore, Chinese migrants to Westernised countries have an increased risk of metabolic diseases compared to those in their country of origin(1,2). We propose that this increased risk is due to a greater manifestation of metabolic abnormalities in response to altered diet and lifestyle behaviours. Although fasting lipaemia and glycaemia are commonly used to predict risk of CVD and T2DM, assessment of impaired postprandial metabolism has been found to be a more sensitive indicator of risk(3). We hypothesised that Chinese migrants, at risk of T2DM, exhibit impaired postprandial lipid and lipoprotein metabolism compared to Australian-born Caucasian counterparts. Chinese and Caucasian adults at risk of T2DM were recruited to the study in which postprandial lipaemia and glycaemia were monitored following consumption of a high fat and high carbohydrate breakfast meal followed by a mixed, lunch meal. In a nonrandomised acute crossover trial, 15 adults (n = 8 Chinese and n = 7 Caucasian) aged ≥ 18 and ≤ 65 years at risk of T2DM (AUSDRISK score > 12 (median = 14.0, IQR = 3.0)), attended two postprandial test days separated by ≥ 7-day washout period. Test breakfast meals were isocaloric (3.6 MJ), high fat (46% energy from fat, 46% energy from carbohydrates) or high carbohydrate (74% E carbohydrates, 17.5% E fat). Blood samples were collected at baseline (fasting), 180 min and 360 min after consumption of the breakfast meal. The lunch meal (3.7 MJ, 18% E fat, 76% E carbohydrates) was consumed 240 min after baseline. Samples were analysed for lipaemia and glycaemia. Additionally, chylomicron-rich, and VLDL-rich lipoprotein fractions were isolated by sequential ultracentrifugation and chylomicron particle number (apolipoprotein (apo) B48), triacylglycerol (TAG), and total cholesterol were assessed in these fractions. Data were analysed using a mixed between-within-subject analysis of variance. There were no differences in age, and baseline anthropometric measures between groups, apart from the Chinese group exhibiting significantly lower waist circumference and BMI compared to the Caucasian group. There were no differences between groups in blood measures, apart from a higher total- and LDL-cholesterol concentration in the Caucasian compared to the Chinese group (P<0.05). Despite identical fasting TAG concentrations, the Chinese group, compared with the Caucasian group exhibited significantly elevated serum TAG and chylomicron-apo-B48 concentrations at 360 min following both test meals (P<0.01). All other postprandial measures were not different between groups. These findings show that despite having identical or improved fasting glycaemia and lipid profile, the Chinese group exhibited impaired postprandial lipid metabolism which may contributes to their increased risk of metabolic diseases.

Effect of omega-3 fatty acid ethyl esters on postprandial arterial elasticity in patients with familial hypercholesterolemia

Impaired arterial elasticity reflects increased risk of atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH). Treatment with omega-3 fatty acid ethyl esters (ω-3FAEEs) in FH patients has been shown to improve postprandial triglyceride-rich lipoprotein (TRL) metabolism, including TRL-apolipoprotein(a) [TRL-apo(a)]. Whether ω-3FAEE intervention also improves postprandial arterial elasticity in FH has not been demonstrated. We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω-3FAEEs (4g/day) on postprandial arterial elasticity in 20FH subjects following ingestion of an oral fat load. Fasting and postprandial large (C1) and small (C2) artery elasticity at 4 and 6h were measured by pulse contour analysis of the radial artery. The area under-the-curves (AUCs) (0-6h) for C1, C2, plasma triglycerides and TRL-apo(a) were determined using the trapezium rule. Compared with no treatment, ω-3FAEEs significantly increased fasting (+9%, P<0.05) and postprandial C1 at 4h (+13%, P<0.05) and at 6h (+10%, P<0.05), with improvement in the postprandial C1 AUC (+10%, P<0.01). ω-3FAEEs also decreased postprandial triglyceride and TRL-apo(a) AUCs (-17% and-19%, respectively, P<0.05). ω-3FAEEs had no significant effect on fasting and postprandial C2. The change in C1 AUC was inversely associated with the changes in the AUC of triglycerides (r=-0.609, P<0.01) and TRL-apo(a) (r=-0.490, P<0.05). High-dose ω-3FAEEs improves postprandial large artery elasticity in adults with FH. Reduction in postprandial TRL-apo(a) with ω-3FAEEs may contribute to the improvement in large artery elasticity. However, our findings need to be confirmed in a larger population. https://www. com/NCT01577056.

Remnant Indices for Estimating Postprandial Lipidemia in Young Women

Postprandial hyperglycemia is well established as a major risk factor for prediabetes and type 2 diabetes. However, for postprandial hyperlipidemia, no definitive criteria exist, and fasting values of lipids and lipoproteins had limited efficacy for estimating postprandial lipidemia. In the present study, we performed a fat-ingestion test and aimed to propose indices for estimating postprandial lipoprotein metabolism. Methods: Healthy young Japanese women (n=54, age 21.1 ± 1.0 y) with apolipoprotein E phenotype 3/3 were enrolled. They ingested fat cream (OFTT cream™, Jomo, Japan; 1 g/kg as cream, 0.35 g/kg as fat). Venous blood samples were taken before (0 h) and at 0.5, 1, 2, 4, and 6 h after ingestion. Results: The serum triglyceride (TG) level peaked at 2 h and returned to below baseline at 6 h. The remnant-like particle-TG (RP-TG) level increased at 1 h, peaked at 2 h, and returned to baseline at 6 h. The remnant lipoprotein-cholesterol (RLP-C) level increased at 2 h, peaked at 4 h, and returned to baseline at 6 h. The apolipoprotein B48 level increased at 1 h, peaked at 4 h, and did not return to baseline at 6 h. The apolipoprotein B100 concentration slightly decreased at 2 h and increased at 6 h. TG−RP-TG did not change during 6 h, but RP-TG/TG rose at 2–6 h compared to the fasting value. RP-TG/RLP-C increased at 2–4 h and returned to baseline at 6 h. Conclusion: After fat ingestion, while the concentration of non-remnant TG was stable, remnant TG increased. The content of TG per remnant particle increased up to 2 h and decreased from 2 h to 6 h, and the size became smaller. The remnant indices, RP-TG/TG and RP-TG/RLP-C, may be useful for estimating postprandial lipidemia.

Platycodi Radix Beverage Improves Postprandial Lipemic Response Associated With Plasma Bacteria-Derived Extracellular Vesicles in Healthy Adults With an Oral Fat Load

ObjectivesThis study aimed to examine the responsiveness of postprandial triglyceride-rich lipoprotein (TRL) metabolism to Platycodi radix beverage (PR) is associated with the alterations in plasma bacteria-derived extracellular vesicles (EVs) composition.MethodsNinety-six healthy and normolipidemic adults were randomly divided into two groups and consumed PR or placebo for 8 weeks. An oral fat tolerance test was performed before and after the 8-week intervention to access the postprandial lipid response. Plasma TG, chylomicron TG (CM-TG), and lipoprotein lipase (LPL) mass levels were measured at fasting, 3, and 6 hours during the oral fat tolerance test and summarized by computing the area under the curve (AUC). EVs isolated from fasting plasma samples were identified using 16S rRNA sequencing. A linear mixed-effect model was used to analyze the difference between the two groups. TLR clearance responder to PR consumption was defined by QUalitative INteraction Trees (QUINT). Lasso regularized generalized linear model (GLM) was used to find genera associated with the responsiveness.ResultsPR consumption for 8 weeks noticeably decreased AUC (0–3h) values for TG and CM-TG compared to the placebo group. Responders for TRL clearance were defined as subjects having higher LPL mass (150.6 ng/mL) and dietary fat intake (38.5 g/day) at baseline. Responders showed remarkable reductions in AUC (0–6h) values for TG and CM-TG in the PR group compared to the placebo group. Furthermore, GLM analysis demonstrated that the responsiveness of postprandial TRL clearance was accurately predicted by the model consisting of changes in the relative abundance of 16 genera, suggesting the close association between them.ConclusionsThese findings suggest that PR consumption modulates postprandial TRL clearance by altering plasma EV composition in normolipidemic adults with habitually higher fat intake over 38.5 g/day.Funding SourcesThis work was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF), and the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (2012M3A9C4048761).

Role of endogenous incretins in the regulation of postprandial lipoprotein metabolism.

Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Role of VLDL receptor in atherogenesis.

My group previously discovered and characterized the rabbit and human VLDL receptors. For more than 30 years, I have focused on research regarding the functions of VLDL receptors in the fields of lipoprotein metabolism and atherogenesis. In this review, I introduce the roles of VLDL receptors in lipoprotein metabolism under physiological conditions and in atherogenesis under nonphysiological conditions. I propose that the VLDL receptor plays key roles in the metabolism of postprandial remnant lipoproteins in concert with lipoprotein lipase (LPL). Furthermore, I propound a new mechanism for macrophage foam cell formation via VLDL receptors by remnant lipoproteins and lipoprotein(a) [Lp(a)] in addition to scavenger receptor pathways. The VLDL receptor is a so-called macrophage β-VLDL receptor, which is involved in macrophage foam cell formation by remnant lipoproteins. Furthermore, Lp(a) is a VLDL receptor ligand and is directly taken up through macrophage VLDL receptors for macrophage foam cell formation. Additionally, the roles of VLDL receptors in atherogenesis are canvassed. http://links.lww.com/COL/A21.

Abstract 16511: Isocaloric Fructose Restriction Improves Postprandial Chylomicron and VLDL Excursions in Adolescents With Obesity by Reducing Angiopoietin-Like Protein 3 and Apolipoprotein CIII

Introduction: Delayed postprandial triglyceride-rich lipoprotein (TRL) metabolism is associated with increased atherogenic risk. Dietary fructose is a preferred lipogenic substrate which contributes to NAFLD and dyslipoproteinemia. Hypothesis: Isocaloric fructose restriction reduces postprandial TRL excursions in part by affecting the modulation of lipoprotein lipase (LPL) activity and peripheral clearance rates. Methods: We determined the effect of 9 days of isocaloric fructose restriction on fasting and postprandial TRL metabolism markers in obese Latino and African American children (9-18 years old; n=30) with high habitual sugar consumption (&gt;50 g/d). Metabolic assessments were performed on day 0 and day 10 of isocaloric fructose restriction (starch substituted for sugar, same macronutrient composition). To follow postprandial TRL metabolism, after an initial double-sized meal, single-sized meals (providing 67% of daily calories, 15% protein, 35% fat, 50% carbohydrate) were fed every 30 minutes, with blood sampled every hour for 8 hours. Fructose content of meals reduced from 12% on day 0 to 4% on day 10. Paired t-tests compared change from day 0 to day 10 within each child. Results: Fasting TG, apoCIII, and ANGPTL3 reduced by 25%, 28% and 26% respectively (p &lt;0.01). Postprandial AUC of TG, apoCIII, ANGPTL3, VLDL, chylomicrons (apoB48) reduced by 35%, 34%, 40%, 17%, 19% (p &lt;0.01), while no changes were found in fasting or AUC for ANGPTL4, ANGPTL8 nor LPL mass. Conclusions: Short-term isocaloric fructose restriction improved postprandial chylomicron and VLDL metabolism in children with obesity. Specific and selective improvements in ANGPTL3 and apoCIII suggest differential modulation of LPL activity as a putative mechanism that deserves further exploration.

132-OR: Peripheral Serotonin Regulates Dietary Fat Absorption and Intestinal Chylomicron Production

Introduction: Diabetic dyslipidemia is a key feature of insulin resistance and is characterized by overproduction of chylomicron particles by the intestine. Chylomicron output can be regulated by hormones secreted from the intestine. Enterochromaffin cells are specialized enteroendocrine cells that secrete serotonin (5-HT). Gut-derived 5-HT is emerging as a regulator of systemic energy homeostasis by regulating adipose and liver lipid metabolism. Currently, the role of 5-HT on intestinal fat absorption and chylomicron production remains unknown. We hypothesize that 5-HT regulates postprandial intestinal fat absorption and chylomicron production. Methods/Results: Syrian golden hamsters underwent jugular cannulation surgery. The next day, hamsters received an oral fat load (200μl olive oil) followed by intravenous infusion of Triton WR-1339 to prevent lipoprotein clearance. Blood samples were collected prior to and up to 6 hours post fat load. Triglyceride-rich lipoproteins (TRL) which includes chylomicrons were isolated from plasma by density gradient ultracentrifugation and triglyceride (TG) content in this fraction was measured using an enzyme based colorimetric assay. Intravenous administration of 5-HT (1mg/kg) 5 minutes prior to oral fat load increased the rate of plasma TG and TRL-TG accumulation while higher doses of 5-HT (5 and 10mg/kg) produced a transient decrease in plasma TG and TRL-TG accumulation. Treatment with 5-HT4 receptor agonist, Bimu-8 (1mg/kg), increased plasma TG and TRL-TG accumulation. Endogenous 5-HT depletion by para-chloro-phenylalanine (PCPA), an inhibitor of 5-HT synthesis, reduced the rate of TG and TRL-TG accumulation compared to vehicle controls. Furthermore, enhancing 5-HT action by inhibiting 5-HT reuptake with fluoxetine increased the rate of TG and TRL-TG accumulation. Our results demonstrate that 5-HT is a key regulator of postprandial lipoprotein metabolism and could have important implications for diabetic dyslipidemia. Disclosure F. Raka: None. K. Adeli: None. Funding Canadian Institutes of Health Research (967131)

Interesterification of a commonly consumed palm-based hard fat blend does not affect postprandial lipoprotein metabolism in healthy older adults

AbstractInteresterified (IE) fats are widely used to replace partially-hydrogenated fats as hard fats with functional and sensory properties needed for spreads/margarines, baked goods, and confectionary, while avoiding the health hazards of trans fats. Detailed mechanistic work to determine the metabolic effects of interesterification of commonly-consumed hard fats has not yet been done. Earlier studies using fats less commonly consumed have shown either neutral or a lowering effect on postprandial lipaemia. We investigated postprandial lipaemia, lipoprotein remodelling, and triacylglycerol-rich lipoprotein (TRL) fraction apolipoprotein concentrations following a common IE blend of palm oil/kernel fractions versus its non-IE counterpart, alongside a reference monounsaturated (MUFA) oil. A 3-armed, double blind, randomized controlled trial (clinicaltrials.gov NCT03191513) in healthy adults (n = 20; 10 men, 10 women) aged 45–75 y, assessed effects of single meals (897 kcal, 50 g fat, 16 g protein, 88 g carbohydrate) on postprandial plasma triacylglycerol (TAG) concentrations, lipoprotein profiles, and TRL fraction apolipoprotein B48 and TAG concentrations. Test fats were IE 80:20 palm stearin/palm kernel fat, the equivalent non-IE fat, and a high-MUFA reference oil (rapeseed oil, RO). Blood was collected at baseline and hourly for 8 h. Linear mixed modelling was performed, adjusting for treatment order and baseline values (ver. 24.0; SPSS Inc., Chicago, IL, USA). Total 8 h incremental area under the curves (iAUC) for plasma TAG concentrations were lower following IE and non-IE compared with RO (mean difference in iAUC: non-IE vs. RO -1.8 mmol/L.h (95% CI -3.3, -0.2); IE vs. RO -2.6 mmol/L.h (95% CI -5.3, 0.0)), but iAUCs for IE and non-IE were not significantly different. There were no differences between IE and non-IE for chylomicron fraction apoB48 concentrations nor TAG:apoB48 ratio. No differences were observed between IE and non-IE for lipoprotein (VLDL, HDL, LDL) particle size or sub-class particle concentrations. However, LDL particle diameters were reduced at 5 and 6 h following IE vs RO (P &lt; 0.05). XXL- (including chylomicron remnants and VLDL particles), XL- and L-VLDL particle concentrations (average diameters &gt; 75, 64, and 53.6 nm respectively) were higher following IE and non-IE vs. RO at 6 h (P &lt; 0.05) and 8 h postprandially (P &lt; 0.005–0.05). In conclusion, both IE and non-IE palmitic acid-rich fats generated a greater preponderance of pro-atherogenic large TRL remnant particles in the late postprandial phase relative to an oleic acid-rich oil. However, the process of interesterification did not modify postprandial TAG response or lipoprotein metabolism.

Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects

Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140mgsubcutaneously every 2weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P<.0001) and VLDL1 triglyceride (by 15%; P=.018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P=.053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P<.0001) and apolipoprotein B-48 concentration (by 17%; P=.0046) and in "remnant-like particles" cholesterol (by 29%; P<.0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P<.0001) and VLDL2 triglyceride by 29% (P<.0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P<.001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P<.01). Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

The VLDL receptor plays a key role in the metabolism of postprandial remnant lipoproteins

A new concept to account for the process of postprandial remnant lipoprotein metabolism is proposed based on the characteristics of lipoprotein particles and their receptors. The characteristics of remnant lipoprotein (RLP) were investigated using an immuno-separation method. The majority of the postprandial lipoproteins increased after fat intake was shown to be VLDL remnants, not chylomicron (CM) remnants, based on the significantly high ratio of apoB100/apoB48 in the RLP and the high degree of similarity in the particle size of the apoB48 and apoB100 carrying lipoproteins, which fluctuate in parallel during a 6 h period after fat intake. The VLDL receptor was discovered as a receptor for TG-rich lipoprotein metabolism and is located in peripheral tissues such as skeletal muscle, adipose tissue, etc., but not in the liver. Postprandial VLDL particles are strongly bound and internalized into cells expressing the VLDL receptor. Ligands that bind to VLDL receptor, such as LPL and Lp(a), present in RLP. The presence of various specific ligands in VLDL remnants may enhance the capacity for binding to the VLDL receptor, which play the role primarily for energy delivery to the peripheral tissues, but is also a causal factor in atherogenic diseases when excessively and/or continuously remained in plasma.

Hypertriglyceridemia and Non-Alcoholic Fatty Liver Disease in Metabolic Syndrome and Type 2 Diabetes

Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are associated with artherogenic dyslipidemia and abnormal postprandial lipoprotein metabolism which consists with elevated fasting and postprandial triglyceride-rich lipoproteins (TRLs), small dense low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol as cardiovascular disease risk factors. These abnormal lipids concentrations can result from alterations in the production, conversion, or catabolism of lipoprotein particles. Whereas the liver is the central organ in lipogenesis, gluconeogenesis and cholesterol metabolism and the intestine is also a major role in lipoprotein production. However, many research studies demonstrated a variety of pathological conditions focused on the metabolic functions within the liver. As observed in the world population, increase in the prevalence of MetS and T2DM promotes pathophysiological from atherogenic dyslipidemia and cause non-alcoholic fatty liver disease (NAFLD). Alterations in insulin activity, response and signaling are held accountable for these alterations in lipid storage, transport and-oxidation. This review focuses on dysfunctions and alterations in increased lipoprotein production prolongs dyslipidemia, hepatic lipid uptake, storage and metabolism in the clinical of NAFLD in MetS and T2DM patients, and may directly contribute to cause atherogenesis in these patients.

Theobromine does not affect postprandial lipid metabolism and duodenal gene expression, but has unfavorable effects on postprandial glucose and insulin responses in humans

Chocolate consumption is associated with a decreased risk for CVD. Theobromine, a compound in cocoa, may explain these effects as it favorably affected fasting serum lipids. However, long-term effects of theobromine on postprandial metabolism as well as underlying mechanisms have never been studied. The objective was to evaluate the effects of 4-week theobromine consumption (500mg/day) on fasting and postprandial lipid, lipoprotein and glucose metabolism, and duodenal gene expression. In a randomized, double-blind crossover study, 44 healthy men and women, with low baseline HDL-C concentrations consumed 500mg theobromine or placebo daily. After 4-weeks, fasting blood was sampled and subjects participated in a 4-hpostprandial test. Blood was sampled frequently for analysis of lipid and glucose metabolism. In a subgroup of 10 men, 5h after meal consumption duodenal biopsies were taken for microarray analysis. 4-weeks theobromine consumption lowered fasting LDL-C (-0.21mmol/L; P=0.006), and apoB100 (-0.04g/L; P=0.022), tended to increase HDL-C (0.03mmol/L; P=0.088) and increased hsCRP (1.2mg/L; P=0.017) concentrations. Fasting apoA-I, TAG, FFA, glucose and insulin concentrations were unchanged. In the postprandial phase, theobromine consumption increased glucose (P=0.026), insulin (P=0.011) and FFA (P=0.003) concentrations, while lipids and (apo)lipoproteins were unchanged. In duodenal biopsies, microarray analysis showed no consistent changes in expression of genes, pathways or gene sets related to lipid, cholesterol or glucose metabolism. It is not likely that the potential beneficial effects of cocoa on CVD can be ascribed to theobromine. Although theobromine lowers serum LDL-C concentrations, it did not change fasting HDL-C, apoA-I, or postprandial lipid concentrations and duodenal gene expression, and unfavorably affected postprandial glucose and insulin responses. This trial was registered on clinicaltrials.gov under study number NCT02209025.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

Breaking up sedentary time, physical activity and lipoprotein metabolism.

Some authors report delayed responses of lipid metabolism after prolonged and interrupted sitting. To date no experimental studies have shown acute physical activity (PA) related changes of lipoprotein metabolism during sedentary behavior (SB). The purpose of this study was to examine immediate effects of a single PA-bout vs. regular PA-breaks on lipoprotein metabolism during postprandial SB. Eighteen female subjects (25.6years±2.6; 21.5kg/m2±2.0) participated in a balanced crossover experiment with three trials: (1) 30min PA prior to 4h sitting (PRE), (2) 5×6min PA within 4h sitting (BREAK) (3) 4h sitting (CTRL). PA was ergometer cycling at 70%VO2max. Participants consumed one standardized breakfast in each trial. Total cholesterol (tChol), high density lipoprotein (HDL), low density lipoprotein (LDL) and triacylglycerol (TAG) readings were taken in fasted state at the beginning (before), and immediately after each trial. Multiple 2×3-ANOVAs (trial-arm*time) and post hoc t-tests were used. ANOVAs revealed trial*time-effects for tChol (p=0.043) and HDL (p=0.007) and a tendency for LDL (p=0.078). Before-to-after differences (Δ) of tChol during BREAK-trial (-0.89±5.49mg/dl) significantly differed to Δ during PRE-trial (+3.56±5.32mg/dl) (p=0.005) but not to ΔCTRL (+2.16±8.72). ΔHDL during BREAK-trial (-2.11±3.31mg/dl) significantly differed to ΔPRE (+0.83±4.26mg/dl) (p=0.007) and ΔCTRL (+0.06±4.15mg/dl) (p=0.028). Analysis of TAG revealed a time effect (p=0.007) and significant differences between TAG before and after trial within BREAK (79.22±38.69mg/dl to 94.78±44.86mg/dl) and CTRL (80.94±32.94mg/dl to 97.72±41.19mg/dl) but not in PRE (78.83±33.13mg/dl to 89.06±33.83mg/dl). Breaking sedentary behavior with vigorous intensity PA seem to decelerate postprandial lipoprotein metabolism during sitting. In contrast, prior PA, might be a stimulus for lipid metabolization.

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

The consequences of angiopoietin-like protein 3 (ANGPTL3) deficiency on postprandial lipid and lipoprotein metabolism has not been investigated in humans. We studied 7 homozygous (undetectable circulating ANGPTL3 levels) and 31 heterozygous (50% of circulating ANGPTL3 levels) subjects with familial combined hypolipidemia (FHBL2) due to inactivating ANGPTL3 mutations in comparison with 35 controls. All subjects were evaluated at fasting and during 6 h after a high fat meal. Postprandial lipid and lipoprotein changes were quantified by calculating the areas under the curve (AUCs) using the 6 h concentration data. Plasma changes of β-hydroxybutyric acid (β-HBA) were measured as marker of hepatic oxidation of fatty acids. Compared with controls, homozygotes showed lower incremental AUCs (iAUCs) of total TG (-69%, P < 0.001), TG-rich lipoproteins (-90%, P < 0.001), apoB-48 (-78%, P = 0.032), and larger absolute increase of FFA (128%, P < 00.1). Also, heterozygotes displayed attenuated postprandial lipemia, but the difference was significant only for the iAUC of apoB-48 (-28%; P < 0.05). During the postprandial period, homozygotes, but not heterozygotes, showed a lower increase of β-HBA. Our findings demonstrate that complete ANGPTL3 deficiency associates with highly reduced postprandial lipemia probably due to faster catabolism of intestinally derived lipoproteins, larger expansion of the postprandial FFA pool, and decreased influx of dietary-derived fatty acids into the liver. These results add information on mechanisms underlying hypolipidemia in FHBL2.

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study.

Background/aimsPrevious evidences have shown the presence of a prolonged and exaggerated postprandial response in type 2 diabetes mellitus (T2DM) and its relation with an increase of cardiovascular risk. However, the response in prediabetes population has not been established. The objective was to analyze the degree of postprandial lipemia response in the CORDIOPREV clinical trial (NCT00924937) according to the diabetic status.Methods1002 patients were submitted to an oral fat load test meal (OFTT) with 0.7 g fat/kg body weight [12 % saturated fatty acids (SFA), 10 % polyunsaturated fatty acids (PUFA), 43 % monounsaturated fatty acids (MUFA), 10 % protein and 25 % carbohydrates]. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 h during postprandial state. Postprandial triglycerides (TG) concentration at any point >2.5 mmol/L (220 mg/dL) has been established as undesirable response. We explored the dynamic response in 57 non-diabetic, 364 prediabetic and 581 type 2 diabetic patients. Additionally, the postprandial response was evaluated according to basal insulin resistance subgroups in patients non-diabetic and diabetic without pharmacological treatment (N = 642).ResultsPrevalence of undesirable postprandial TG was 35 % in non-diabetic, 48 % in prediabetic and 59 % in diabetic subgroup, respectively (p < 0.001). Interestingly, prediabetic patients displayed higher plasma TG and large triacylglycerol-rich lipoproteins (TRLs-TG) postprandial response compared with those non-diabetic patients (p < 0.001 and p = 0.003 respectively). Moreover, the area under the curve (AUC) of TG and AUC of TRLs-TG was greater in the prediabetic group compared with non-diabetic patients (p < 0.001 and p < 0.005 respectively). Patients with liver insulin resistance (liver-IR) showed higher postprandial response of TG compared with those patients with muscle-IR or without any insulin-resistance respectively (p < 0.001).ConclusionsOur findings demonstrate that prediabetic patients show a lower phenotypic flexibility after external aggression, such as OFTT compared with nondiabetic patients. The postprandial response increases progressively according to non-diabetic, prediabetic and type 2 diabetic state and it is higher in patients with liver insulin-resistance. To identify this subgroup of patients is important to treat more intensively in order to avoid future cardiometabolic complications.

Phytosterols, Phytostanols, and Lipoprotein Metabolism

The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL) cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%–10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a) or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL) cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein particles will be diminished.

Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome

Diabetes and metabolic syndrome are associated with abnormal postprandial lipoprotein metabolism, with a significant delay in the clearance of many lipid parameters, including triglycerides and chylomicrons. Abnormal concentrations of plasma lipids can result from changes in the production, conversion, or catabolism of lipoprotein particles. Whereas the liver is involved in controlling serum lipid levels through synthesis of liver derived triglyceride-rich lipoproteins and low-density lipoprotein metabolism, the intestine also has a major role in lipoprotein production. Postprandial lipemia results from increases in apoB-48 availability, lipogenesis, and the synthesis and absorption of cholesterol in the enterocytes. Increased intestinal lipoprotein production prolongs postprandial lipemia in patients with diabetes and MetS, and may contribute directly to atherogenesis in these patients.

The ingestion of a fructose-containing beverage combined with fat cream exacerbates postprandial lipidemia in young healthy women.

To investigate the acute effects of the ingestion of a fructose-containing beverage combined with fat on postprandial lipoprotein metabolism. Twelve young healthy Japanese women with apolipoprotein E phenotype 3/3 were enrolled in this study. At each of four sessions, the subjects ingested one of four sugar beverages containing fructose and/or glucose (total: 0.5 g/kg body weight) combined with OFTT cream (1 g/kg, 0.35 g/kg as fat) in a randomized crossover design. The four sugar beverages were as follows: 100% (w/w) fructose (F100), 90% fructose + 10% glucose (F90G10), 55% fructose + 45% glucose (F55G45) and 100% glucose (G100). Venous blood samples were obtained at baseline and 0.5, one, two, four and six hours after ingestion. The serum concentrations of TG in the F100, F90G10 and F55G45 trials were significantly higher than each fasting value at two and four hours, and returned to baseline at six hours, except in the F100 trial. The concentrations at four hours and the incremental areas under the curve for the hepatic triglyceride-rich lipoprotein-triglyceride (VLDL-TG(TM)) levels in the F100 and F90G10 trials were significantly higher and larger, respectively, than those observed in the G100 trial. Meanwhile, the concentrations of RLP-TG and apolipoprotein B-48 peaked at two hours in the G100 trial, versus four hours in the other trials, and did not return to baseline at six hours, except in the G100 trial. At four hours, the ⊿apoB48 tended to be higher in the F100 trial than in the G100 trial. The ingestion of a high-fructose-containing beverage with fat cream delays the clearance of chylomicron and its remnant derived from the intestine and enhances the secretion of triglyceride-rich lipoprotein particles from the liver, thereby inducing postprandial lipidemia, even in young healthy women.