Chylomicron Triacylglycerol Research Articles

SHR-Zbtb16 minimal congenic strain reveals nutrigenetic interaction between Zbtb16 and high-sucrose diet.

Both prenatal and postnatal excessive consumption of dietary sucrose or fructose was shown to be detrimental to health and contributing to pathogenesis of metabolic syndrome. Our knowledge of genetic determinants of individual sensitivity to sucrose-driven metabolic effects is limited. In this study, we have tested the hypothesis that a variation of metabolic syndrome-related gene, Zbtb16 (Zinc Finger and BTB Domain Containing 16 will affect the reaction to high-sucrose diet (HSD) content in "matched" nutritional exposition settings, i.e. maternal HSD with re-exposition to HSD in adulthood vs. standard diet. We compared metabolic profiles of adult males of spontaneously hypertensive rats (SHR) and a single-gene, minimal congenic strain SHR-Zbtb16 fed either standard diet or exposed to HSD prenatally throughout gestation and nursing and again at the age of 6 months for the period of 14 days. HSD exposition led to increased adiposity in both strains and decrease of glucose tolerance and cholesterol (Ch) concentrations in majority of low-density lipoprotein (LDL) particle classes and in very large and large high-density lipoprotein (HDL) in SHR-Zbtb16 male offspring. There was a similar pattern of HSD-induced increase of triacylglycerols in chylomicrons and very low-density lipoprotein (VLDL) of both strains, though the increase of (triacylglycerol) TAG content was clearly more pronounced in SHR. We observed significant STRAIN*DIET interactions for the smallest LDL particles as their TAG content decreased in SHR-Zbtb16 and did not change in SHR in response to HSD. In summary, we provide evidence of nutrigenetic interaction between Zbtb16 and HSD in context of pathogenesis of metabolic syndrome.

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 < 0.05). XXL- (including chylomicron remnants and VLDL particles), XL- and L-VLDL particle concentrations (average diameters > 75, 64, and 53.6 nm respectively) were higher following IE and non-IE vs. RO at 6 h (P < 0.05) and 8 h postprandially (P < 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.

Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study

Aims/hypothesisThe study aimed to examine the efficacy of 12 weeks of monthly evolocumab or placebo in lowering LDL-cholesterol (LDL-C) in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia and on a maximum-tolerated statin of at least moderate intensity.MethodsFor this randomised, placebo-controlled outpatient study, eligible individuals were ≥18 years old with type 2 diabetes, HbA1c <10% (86 mmol/mol), had been on stable pharmacological therapy for diabetes for ≥6 months and were taking a maximum-tolerated statin dose of at least moderate intensity. Lipid eligibility criteria varied by history of clinical cardiovascular disease. Participants were randomised 2:1 to evolocumab 420 mg s.c. or placebo. Randomisation was performed centrally via an interactive web-based or voice recognition system. Allocation was concealed using the centralised randomisation process. Treatment assignment was blinded to the sponsor study team, investigators, site staff and patients throughout the study. Co-primary endpoints were mean percentage change in LDL-C from baseline to week 12 and to the mean of weeks 10 and 12. Additional endpoints included LDL-C <1.81 mmol/l, LDL-C reduction ≥50% and other lipids. Exploratory analyses included percentage changes in fasting and post mixed-meal tolerance test (MMTT) lipoproteins and lipids, glucose metabolism variables and inflammatory biomarkers.ResultsIn total, 421 individuals were randomised and analysed, having received evolocumab (280 participants) or placebo (141 participants) (mean [SD] age 62 [8] years; 44% women; 77% white). Evolocumab decreased LDL-C by 54.3% (1.4%) at week 12 (vs 1.1% [1.9%] decrease with placebo; p < 0.0001) and by 65.0% (1.3%) at the mean of weeks 10 and 12 (vs 0.8% [1.8%] decrease with placebo; p < 0.0001); it also decreased non-HDL-cholesterol (HDL-C) by 46.9% (1.3%) at week 12 (vs 0.6% [1.8%] decrease with placebo) and by 56.6% (1.2%) at the mean of weeks 10 and 12 (vs 0.1% [1.6%] decrease with placebo). Evolocumab significantly improved levels of other lipids and allowed more participants to reach LDL-C <1.81 mmol/l or a reduction in LDL-C levels ≥50%. After an MMTT (120 min), there were favourable changes (p < 0.05; nominal, post hoc, no multiplicity adjustment) in chylomicron triacylglycerol (triglycerides), chylomicron cholesterol, VLDL-C and LDL-C. Evolocumab had no effect on glycaemic variables and was well tolerated.Conclusions/interpretationIn statin-treated individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia, evolocumab significantly reduced LDL-C and non-HDL-C. Favourable changes (p < 0.05) were observed in postprandial levels of chylomicrons, VLDL-C and LDL-C.Trial registrationClinicalTrials.gov NCT02739984FundingThis study was funded by Amgen Inc.Data availabilityQualified researchers may request data from Amgen clinical studies. Complete details are available at www.amgen.com/datasharing.

Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance.

ContextGlucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.ObjectiveTo determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes.DesignRandomized, double-blind, cross-over study.SettingCentre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom.PatientsEight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)].InterventionsTwo metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies.Main Outcome MeasuresStudy one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion.ResultsStudy one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60–480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0–240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0–360min (P = 0.006) were lower with lixisenatide than with placebo.ConclusionsLixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Angiopoietin-Like Protein 4 and Postprandial Skeletal Muscle Lipid Metabolism in Overweight and Obese Prediabetics.

Angiopoietin-like protein 4 (ANGPTL4) decreases plasma triacylglycerol (TAG) clearance by inhibiting lipoprotein lipase (LPL) and may contribute to impairments in lipid metabolism under compromised metabolic conditions. To investigate the effects of a high-saturated fatty acid (SFA) mixed meal on plasma ANGPTL4 concentrations in relation to in vivo muscle LPL activity, to study the effects of dietary fat quality, and to examine skeletal muscle ANGPTL4 release. Design, Participants, Setting, and Interventions: We used a dual stable-isotope tracer technique in combination with measurements of arteriovenous concentration differences across forearm muscle to investigate muscle ANGPTL4 secretion and fatty acid handling under fasting conditions and after a high-SFA mixed meal in 73 overweight and obese humans at the Metabolic Research Unit of Maastricht University. The effect of dietary fat quality manipulation on plasma ANGPTL4 was investigated in 10 obese insulin-resistant participants. The high-SFA meal decreased circulating ANGPTL4 concentrations (fasting, 5.2 ng/mL; vs 4 hours postprandial, 4.0 ng/mL; P < .001). Furthermore, skeletal muscle ANGPTL4 secretion into the circulation was observed (AUC0-4 h, P = .048). However, no association was observed between plasma ANGPTL4 and skeletal muscle very low-density lipoprotein or dietary (chylomicron) TAG extraction (AUC0-4 h, P = .372 and P = .139, respectively). In contrast to a high-SFA or high-monounsaturated fat meal, plasma ANGPTL4 remained unchanged after a high-polyunsaturated fat meal. ANGPTL4 is secreted by human forearm muscle in postprandial conditions after a high-SFA meal. Plasma ANGPTL4 concentrations were not associated with in vivo skeletal muscle LPL activity after a high-SFA meal. Dietary fat quality affects plasma ANGPTL4, but it remains to be elucidated whether this influences short-term skeletal muscle lipid handling.

The Postprandial Chylomicron Triacylglycerol Response to Dietary Fat in Healthy Male Adults Is Significantly Explained by a Combination of Single Nucleotide Polymorphisms in Genes Involved in Triacylglycerol Metabolism

The postprandial chylomicron (CM) triacylglycerol (TG) response to dietary fat, which is positively associated with atherosclerosis and cardiovascular disease risk, displays a high interindividual variability. This is assumed to be due, at least partly, to polymorphisms in genes involved in lipid metabolism. Existing studies have focused on single nucleotide polymorphisms (SNPs), resulting in only a low explained variability. We aimed to identify a combination of SNPs associated with the postprandial CM TG response. Thirty-three healthy male volunteers were subjected to 4 standardized fat tolerance test meals (to correct for intraindividual variability) and genotyped using whole-genome microarrays. The plasma CM TG concentration was measured at regular interval times after each meal. The association of SNPs in or near candidate genes (126 genes representing 6225 SNPs) with the postprandial CM TG concentration (0-8 h areas under the curve averaged for the 4 test meals) was assessed by partial least squares regression, a multivariate statistical approach. Data obtained allowed us to generate a validated significant model (P = 1.3 × 10(-7)) that included 42 SNPs in 23 genes (ABCA1, APOA1, APOA5, APOB, BET1, CD36, COBLL1, ELOVL5, FRMD5, GPAM, INSIG2, IRS1, LDLR, LIPC, LPL, LYPLAL1, MC4R, NAT2, PARK2, SLC27A5, SLC27A6, TCF7L2, and ZNF664) and explained 88% of the variance. In 39 of these SNPs, univariate analysis showed that subjects with different genotypes exhibited significantly different (q < .05) postprandial CM TG responses. Using a multivariate approach, we report a combination of SNPs that explains a significant part of the variability in the postprandial CM TG response.

Apolipoprotein A-IV Reduces Hepatic Gluconeogenesis through Nuclear Receptor NR1D1

We showed recently that apoA-IV improves glucose homeostasis by enhancing pancreatic insulin secretion in the presence of elevated levels of glucose. Therefore, examined whether apolipoprotein A-IV (apoA-IV) also regulates glucose metabolism through the suppression of hepatic gluconeogenesis. The ability of apoA-IV to lower gluconeogenic gene expression and glucose production was measured in apoA-IV(-/-) and wild-type mice and primary mouse hepatocytes. The transcriptional regulation of Glc-6-Pase and phosphoenolpyruvate carboxykinase (PEPCK) by apoA-IV was determined by luciferase activity assay. Using bacterial two-hybrid library screening, NR1D1 was identified as a putative apoA-IV-binding protein. The colocalization and interaction between apoA-IV and NR1D1 were confirmed by immunofluorescence, in situ proximity ligation assay, and coimmunoprecipitation. Enhanced recruitment of NR1D1 and activity by apoA-IV to Glc-6-Pase promoter was verified with ChIP and a luciferase assay. Down-regulation of apoA-IV on gluconeogenic genes is mediated through NR1D1, as illustrated in cells with NR1D1 knockdown by siRNA. We found that apoA-IV suppresses the expression of PEPCK and Glc-6-Pase in hepatocytes; decreases hepatic glucose production; binds and activates nuclear receptor NR1D1 and stimulates NR1D1 expression; in cells lacking NR1D1, fails to inhibit PEPCK and Glc-6-Pase gene expression; and stimulates higher hepatic glucose production and higher gluconeogenic gene expression in apoA-IV(-/-) mice. We conclude that apoA-IV inhibits hepatic gluconeogenesis by decreasing Glc-6-Pase and PEPCK gene expression through NR1D1. This novel regulatory pathway connects an influx of energy as fat from the gut (and subsequent apoA-IV secretion) with inhibition of hepatic glucose production.

Prandial Hypertriglyceridemia in Metabolic Syndrome Is Due to an Overproduction of Both Chylomicron and VLDL Triacylglycerol

The aim was to determine whether fed VLDL and chylomicron (CM) triacylglycerol (TAG) production rates are elevated in metabolic syndrome (MetS). Eight men with MetS (BMI 29.7 ± 1.1) and eight lean age-matched healthy men (BMI 23.1 ± 0.4) were studied using a frequent feeding protocol. After 4 h of feeding, an intravenous bolus of 2H5-glycerol was administered to label VLDL1, VLDL2, and TAG. 13C-glycerol tripalmitin was administered orally as an independent measure of CM TAG metabolism. Hepatic and intestinal lipoproteins were separated by an immunoaffinity method. In MetS, fed TAG and the increment in TAG from fasting to feeding were higher (P = 0.03 and P = 0.04, respectively) than in lean men. Fed CM, VLDL1, and VLDL2 TAG pool sizes were higher (P = 0.006, P = 0.03, and P < 0.02, respectively), and CM, VLDL1, and VLDL2 TAG production rates were higher (P < 0.002, P < 0.05, and P = 0.06, respectively) than in lean men. VLDL1, VLDL2, and CM TAG clearance rates were not different between groups. In conclusion, prandial hypertriglyceridemia in men with MetS was due to an increased production rate of both VLDL and CM TAG. Since both groups received identical meals, this suggests that in MetS the intestine is synthesizing more TAG de novo for export in CMs.

A novel method for measuring intestinal and hepatic triacylglycerol kinetics

This study aimed to 1) develop a method that completely separated hepatic (VLDL1, VLDL2) and intestinal [chylomicron (CM)] lipoproteins and 2) use the method to measure triacylglycerol (TAG) kinetics in these lipoproteins in the fed and fasting state in healthy subjects, using intravenous [²H₅]glycerol as the tracer. An immunoaffinity method that completely separated hepatic and intestinal particles using sequential binding to three antibodies to apolipoprotein B-100 (apoB-100) was established and validated. Six healthy volunteers were studied in a fasted and continuous feeding study (study 1). Five additional healthy volunteers were studied in a continuous feeding study that included an oral [¹³C₃]glycerol tripalmitin tracer (study 2). In both studies, an intravenous bolus of [²H₅]glycerol was administered to label TAG in hepatic and intestinal lipoproteins. In both feeding studies there was sufficient incorporation of the [²H₅]glycerol tracer into the exogenous lipoproteins to enable isotopic enrichment to be measured. In study 2, the oral tracer enrichment in VLDL1 was <5% of CM enrichment 150 min after tracer administration, demonstrating negligible contamination of VLDL1 with apoB-48. Western blotting showed no detectable apoB-100 in CMs. VLDL1 and VLDL2 TAG fractional catabolic rate (FCR) did not differ between feeding and fasting (study 1). There was no difference between CM and VLDL1 TAG FCR in both fed studies. In fed study 2, 47% of the total TAG production rate (CM + VLDL1) was from CM. This methodology may be a useful tool for understanding the abnormalities in postprandial TAG kinetics in metabolic syndrome and type 2 diabetes.

The Effects of Long-Term Valsartan Treatment on Skeletal Muscle Fatty Acid Handling in Humans With Impaired Glucose Metabolism

Blocking the renin-angiotensin system reduces the incidence of type 2 diabetes mellitus in humans with impaired glucose metabolism (IGM). Nevertheless, underlying mechanisms remain to be established. The purpose of this study was to investigate the effects of the angiotensin II type 1 receptor blocker valsartan (VAL) on skeletal muscle fatty acid (FA) handling in subjects with IGM. This was a randomized, double-blind placebo-controlled trial at Maastricht University Medical Center. INTERVENTION/MAIN OUTCOMES/PARTICIPANTS: Fasting and postprandial skeletal muscle FA handling were assessed at baseline and after 26 weeks of treatment with VAL or placebo in 26 subjects with IGM. Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm balance technique with stable isotopes of palmitate. [²H₂]-Palmitate was infused iv to label endogenous triacylglycerol (TAG) and free fatty acid (FFA) in the circulation, and [U-¹³C]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61% energy from fat) to label chylomicron TAG. Muscle biopsy samples were taken to determine im TAG, diacylglycerol (DAG), FFA, and phospholipid contents, their fractional synthetic rates and degree of saturation, and mRNA expression of oxidative genes. VAL decreased saturation of im TAG and DAG fractions but did not affect net muscle uptake of [²H₂]-palmitate, very low-density lipoprotein ([²H₂])-TAG and chylomicron ([U-¹³C])-TAG, and muscle mRNA expression. VAL decreased FA spillover, as estimated by circulating [U-¹³C]-palmitate, and FFA rate of appearance and tended to decrease chylomicron TAG concentrations. VAL treatment for 26 weeks decreased saturation of skeletal muscle TAG and DAG stores, suggesting altered intramuscular lipid partitioning of FA. The VAL-induced reduction in postprandial FA spillover, endogenous lipolysis, and chylomicron TAG concentrations indicate improved adipose tissue lipid buffering capacity.

Lipidomic Profiling of Chylomicron Triacylglycerols in Response to High Fat Meals

Using lipidomic methodologies the impact that meal lipid composition and metabolic syndrome (MetS) exerts on the postprandial chylomicron triacylglycerol (TAG) response was examined. Males (9 control; 11 MetS) participated in a randomised crossover trial ingesting two high fat breakfast meals composed of either dairy-based foods or vegetable oil-based foods. The postprandial lipidomic molecular composition of the TAG in the chylomicron-rich (CM) fraction was analysed with tandem mass spectrometry coupled with liquid chromatography to profile CM TAG species and targeted TAG regioisomers. Postprandial CM TAG concentrations were significantly lower after the dairy-based foods compared with the vegetable oil-based foods for both control and MetS subjects. The CM TAG response to the ingested meals involved both significant and differential depletion of TAG species containing shorter- and medium-chain fatty acids (FA) and enrichment of TAG molecular species containing C16 and C18 saturated, monounsaturated and diunsaturated FA. Furthermore, there were significant changes in the TAG species between the food TAG and CM TAG and between the 3- and 5-h postprandial samples for the CM TAG regioisomers. Unexpectedly, the postprandial CM TAG concentration and CM TAG lipidomic responses did not differ between the control and MetS subjects. Lipidomic analysing of CM TAG molecular species revealed dynamic changes in the molecular species of CM TAG during the postprandial phase suggesting either preferential CM TAG species formation and/or clearance.

The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols

The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P=0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P=0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P=0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.

Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study

Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal. Seventy-one patients (age 18-70 years), who did not reach HbA(1c) 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0 mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo (n = 25), Alo/Pio (n = 22) or Pbo (n = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion. At week 16, Alo (n = 25) and Alo/Pio (n = 21) vs Pbo (n = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p < 0.001), as well as in chylomicron TG (p < 0.001) and VLDL1 TG iAUCs (p < 0.001 and p = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p = 0.028), and a non-significant trend towards a decrease with Alo/Pio (p = 0.213). The incidence of adverse events was low and consistent with previous studies. Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells. ClinicalTrials.gov number NCT00655863.

Marine phospholipids as dietary carriers of long‐chain polyunsaturated fatty acids

AbstractEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are polyunsaturated fatty acids (PUFA) of the n‐3 series. Fish oil is a classical source of n‐3 PUFA, where they occur in the form of triacylglycerols (TAG). However, new sources of n‐3 PUFA esterified in phospholipids (PL) are emerging. We prepared liposomes from a natural marine lipid extract and examined their behaviour under conditions mimicking that of the gastrointestinal tract. This physicochemical approach proved that liposomes could be used as an effective oral PUFA delivery system. In vivo studies in rats were performed to examine the metabolic fate of EPA (20:5 n‐3) and DHA (22:6 n‐3) delivered either in PL from liposomes or in TAG from oil. Liposome ingestion increased PUFA bioavailability in lymph compared with fish oil. The proportion of n‐3 PUFA esterified in the sn‐2 position of chylomicron TAG depended on the dietary lipid source. Complex time‐course profiles were observed for plasma lipids with liposome supplementation over a 2‐week period, suggesting time‐dependent regulations. Taken together, the type of PUFA, EPA or DHA, as well as its intramolecular distribution in chylomicron TAG seemed to influence the metabolic fate of the fatty acids and their physiological activities.

Intestinal absorption of dietary maize glucosylceramide in lymphatic duct cannulated rats

Sphingolipids are ubiquitous in all eukaryotic organisms. Various physiological functions of dietary sphingolipids, such as preventing colon cancer and improving the skin barrier function, have been recently reported. One of the common sphingolipids used as a foodstuff is glucosylceramide from plant sources, which is composed of sphingoid bases distinct from those of mammals. However, the fate of dietary sphingolipids derived from plants is still not understood. In this study, we investigated the absorption of maize glucosylceramide in the rat intestine using a lipid absorption assay of lymph from the thoracic duct. The free and complex forms of trans-4,cis-8-sphingadienine, the predominant sphingoid base of maize glucosylceramide, were found in the lymph after administration of maize glucosylceramide. This plant type of sphingoid base was detected in the ceramide fraction and N-palmitoyl-4,8-sphingadienine (C16:0-d18:2) and N-tricosanoyl-4,8-sphingadienine (C23:0-d18:2) were identified by LC-MS/MS. The cumulative recovery of 4t,8c-sphingadienine in the lymph was very low. These results indicate that dietary glucosylceramide originating from higher plants is slightly absorbed in the intestine and is incorporated into ceramide structures in the intestinal cells. However, it appears that the intact form of sphingoid bases is not reutilized well in the tissues.

Hypolipidemic Effect of Pleurotus eryngii Extract in Fat-Loaded Mice

Pleurotus eryngii water extract (PEE), which showed the most significant inhibitory activity against pancreatic lipase in vitro among eight edible mushrooms, was investigated to determine the mechanism of its anti-lipase activity in vitro and its hypolipidemic effect in fat-loaded mice. The inhibitory effects of mushroom extracts on pancreatic lipase activity were examined using 4-methylumbelliferyl oleate (4-MUO) or trioleoylglycerol emulsified with lecithin, gum arabic or Triton X-100 as a substrate. For in vivo experiments, blood samples were taken after oral administration of corn oil and [(3)H]trioleoylglycerol with or without PEE to food-deprived mice. PEE inhibited hydrolysis of 4-MUO and trioleoylglycerol emulsified with lecithin or Triton X-100, but not that of trioleoylglycerol emulsified with gum arabic. PEE suppressed the elevations of plasma and chylomicron triacylglycerol levels after oral administration of corn oil, but had no effect on lipoprotein lipase activity. [(3)H]Trioleoylglycerol absorption was also decreased by administration of PEE. The results of in vitro studies suggest that PEE may prevent interactions between lipid emulsions and pancreatic lipase. The hypolipidemic effect of PEE in fat-loaded mice may be due to low absorption of fat caused by the inhibition of pancreatic lipase.

Exercise prior to fat ingestion lowers fasting and postprandial VLDL and decreases adipose tissue IL-6 and GIP receptor mRNA in hypertriacylglycerolemic men

Fasting and postprandial triacylglycerol (TAG) concentrations are risk factors for cardiovascular disease. This study evaluated whether interleukin-6 (IL-6) and incretin hormones [gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) (active)] were associated with fasting and postprandial TAG in response to an oral lipid load, including very-low-density lipoprotein (VLDL) and chylomicron (CM) TAG, following one bout of exercise in nine men (age, 59±2 years; body mass index, 34±2 kg/m 2; waist circumference, 113±3 cm) with high fasting TAG (2.9±0.2 mmol/L). Subjects completed two oral fat tolerance tests (OFTTs), randomized 1 week apart, that consisted of 1g fat/kg body weight emulsified lipids in the absence of carbohydrate and protein. Approximately 16 h prior to one OFTT, subjects completed 60 min of treadmill walking (estimated 55% VO 2 peak; heart rate, 122±4 beats/min). No exercise was performed on the day before the other OFTT. Fasted (0 h) and postprandial (1, 2, 3, 4, 5 and 6 h) blood samples were taken for analysis of TAG, IL-6 and incretins. Subcutaneous adipose tissue biopsies were taken at 0 and 6 h after OFTT ingestion for IL-6 and GIP receptor (GIPr) mRNA quantification. Exercise lowered fasting and postprandial TAG ( P<.05) and VLDL TAG ( P<.05), while postprandial CM TAG were similar in both OFTT trials ( P>.05). Fasting and postprandial plasma IL-6, GIP and GLP-1 did not differ between rest and exercise OFTT trials ( P>.05). Exercise reduced IL-6 and GIPr mRNA ( P<.05) in adipose tissue. Our results suggest that the reduction in VLDL TAG following an acute bout of exercise is not associated with circulating IL-6 or incretin concentrations, despite reductions in the adipose tissue expression of IL-6 and GIPr.

Dose-Response ofn-3 Polyunsaturated Fatty Acids on Lipid Profile and Tolerability in Mildly Hypertriglyceridemic Subjects

The n-3 polyunsaturated fatty acids (PUFAs) are known to reduce risk for coronary heart disease partly by altering blood lipids. The purpose of this study was to determine the effect of low doses of n-3 PUFAs on the lipid profile and their tolerability in mildly hypertriglyceridemic subjects. Subjects with a serum triacylglycerol (TG) level between 100 and 300 mg/dL were placed on a corn oil placebo (seven capsules per day; single-blind) for 4 weeks and then randomized to continue seven capsules per day of placebo (n = 49) or one of the following doses of n-3 PUFAs for 20 weeks: 0.5 g (n = 51), 1 g (n = 23), or 2 g (n = 12). During the treatment period, 48-50% of the 1-g and 2-g dose groups reported noticing burping (P < .05), and only about half as many in the 0.5-g group noticed burping. Interestingly, 2% of those assigned to the placebo did report a fishy burping during the study, but this dropped back to nearly 0% by week 20. There was no significant effect for any dosage group on fasting and postprandial serum TG, chylomicron TG, very-low-density lipoprotein-cholesterol, or high-density lipoprotein-cholesterol concentration. However, 1-g and 2-g n-3 PUFA treatments significantly increased total cholesterol and low-density lipoprotein-cholesterol concentration. In addition, all doses of n-3 PUFA treatments significantly increased plasma phospholipid n-3 PUFAs. We conclude that doses of n-3 PUFAs of 0.5-2 g/day in healthy volunteers with above average TG levels did not have beneficial effects on their lipid profiles.

Postprandial metabolism with 1,3-diacylglycerol oil versus equivalent intakes of long-chain and medium-chain triacylglycerol oils

Objective We assessed the ability of novel lipid structures including medium-chain triacylglycerols (MCTs) and 1,3-diacylglycerol (DG) oil to lower postprandial triacylglycerol (TG) elevation and increase hepatic fat oxidation when substituted for dietary TG, which may be useful in the prevention and treatment of obesity and other related metabolic conditions, such as dyslipidemias. Methods This double-blind, randomized, crossover trial evaluated the effects of an oral fat load containing DG or MCTs compared with equivalent intakes of long-chain triacylglycerols (LCTs) on the postprandial metabolic responses of insulin-resistant men and women ( n = 36). Each subject consumed a single oral fat load on each test day. The fat loads were delivered in milkshakes that contained 30 g of one of the three test oils. Results The postprandial TG incremental area under the curve after MCT was 73% lower, and that for DG was 22% lower, compared with the response after LCT oil. The incremental area under the curve values for chylomicron TG were reduced versus LCT by 89% and 28%, respectively, in the MCT and DG conditions. Compared with the LCT treatment, β-hydroxybutyrate concentration was increased after MCT oil, but not after DG. Conclusion These results indicate that dietary DG decreased postprandial triglyceridemia compared with LCT, but to a lesser extent than MCT.

Regio-distribution of stearic acid is not conserved in chylomicrons after ingestion of randomised, stearic acid-rich fat in a single meal

Stearic acid from conventional food is well absorbed, but the fate of synthetic randomized stearic acid in fat absorption and subsequent metabolism is unclear. In this study, we examined the postprandial triglyceridemia following an ingestion of randomized stearic acid-rich fat. Following a 12-h fast, nine healthy young males ate a hamburger meal with 16.7 g of stearic acid (30% in triacylglycerol (TAG) sn-2 position, fully randomized). Postprandial blood samples were collected for 450 min, and the stearic acid content in chylomicron (CM, Svedberg flotation rate >400) TAG and the proportion of stearic acid in the sn-2 position were measured by tandem mass spectrometry at peak (180 min) and late (360 min) triglyceridemia. Of all stearic acid in CM TAG, 23% and 22% were in the sn-2 position at peak and late triglyceridemia ( P<.004 and P<.001, respectively). This suggests a 68% and 62% conservation of sn-2 stearic acid, respectively. Peak postprandial TAG concentration and incremental area under the TAG curve showed a higher correlation with the fasting CM TAG ( r=0.88, P<.01 and r=0.72, P<.05, respectively) than with total fasting plasma TAG ( r=0.73, P<.05 and r=0.24, nonsignificant, respectively). In an earlier study, we showed that the absorption efficiency of the stearic acid of the meal was normal, with only marginal amounts of mainly sn-1,3 stearic acid found in the feces. In conclusion, we showed that sn-2 stearic acid is underrepresented in the postprandial CM TAG following an ingestion of fully randomized fat.