Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 modulate bile acids and cholesterol metabolism in humans.

AIMS: Probiotics with high bile salt hydrolase (BSH) activity have shown to promote cardiovascular health. However, their mechanism(s) of action remain poorly understood. Here, we performed a pilot exploratory study to investigate effects of a 4-week intervention with escalating doses of a BSH-active formula containing Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 on bile acid (BA), lipid profile, and lipoprotein function. METHODS AND RESULTS: Healthy overweight individuals were included in this study. The probiotic intake was associated with a progressive decrease of conjugated BAs in serum, due to the reduction of tauro- and glyco-conjugated forms. Plasma levels of fibroblast growth factor-19 were significantly reduced and correlated with BA changes. The probiotic induced significant changes in serum lipids, with reduction in non-HDL cholesterol (non-HDLc) and LDL cholesterol (LDLc) levels. The largest decrease was evidenced in the subgroup with higher baseline LDLc levels (LDLc > 130 mg/dL). Fasting levels of circulating apolipoprotein(Apo) B100 and ApoB48 were significantly reduced. Importantly, the decrease in non-HDLc levels was associated with a significant reduction in small LDL particles. Functional testing indicated that LDL particles had a significantly lower susceptibility to oxidation, while HDL particles gained antioxidant capacity after the probiotic intake. The microbiota profile in faeces collected at the end of the study was enriched with members of class Desulfovibrio, a taurine-consuming bacteria, likely because of the increase in free taurine in the gut due to the BSH activity of the probiotic. CONCLUSION: The intervention with L. plantarum strains induces beneficial effects on BA signature and lipoprotein profile. It reduces ApoB and small LDL levels and LDL susceptibility to oxidation and increases HDL antioxidant capacity. These metabolic profile changes suggest increased protection against atherosclerotic disease.

Matrix structure of dairy products results in different postprandial lipid responses: a randomized crossover trial.

BACKGROUND: The dairy matrix may influence digestion and absorption of lipids and thereby risk of cardiovascular diseases (CVDs). However, few postprandial studies have compared dairy products that differed only in terms of their matrix. OBJECTIVES: We aimed to investigate acute 8-h postprandial lipid, glycemic, and appetite responses after intake of isoenergetic dairy meals with different matrixes, but similar nutritional composition. METHODS: Twenty-five normal-weight men (18-40 y old) were enrolled in a randomized controlled crossover trial. On 4 test days, a meal with 1 of 4 dairy products was served: cheddar cheese (Cheese), homogenized Cheese (Hom. Cheese), micellar casein isolate (MCI) with cream (MCI Drink), and a gel produced from the MCI Drink by addition of Glucono Delta-Lactone (MCI Gel). The fat- and protein-matched dairy products differed in terms of their casein network, fat droplet size, and/or texture. Blood biochemistry and appetite responses were collected. RESULTS: Eighteen participants completed the trial. Postprandial triglycerides (TGs) (primary outcome) increased by (mean ± SEM) 0.24 ± 0.07 and 0.19 ± 0.07 mmol/L after MCI Gel compared with Cheese and Hom. Cheese, respectively (both P ≤ 0.05). Likewise, MCI Gel increased TG incremental AUC compared with Cheese and Hom. Cheese (both P < 0.05), and peak compared with Cheese (P < 0.05). ApoB-48 (primary outcome) was unaffected by dairy matrix. For free fatty acids (FFAs), glucose, and insulin, time × meal interactions were observed (all P < 0.001). During the first 2 h, FFAs were lower for Cheese than for MCI products, whereas the opposite was observed for glucose and insulin. CONCLUSIONS: Postprandial TG but not apoB-48 response was higher after MCI Gel, indicating that the type of casein network influences lipid responses. This suggests that the dairy matrix may also affect risk factors for CVDs. Reducing fat droplet size (i.e., Hom. Cheese) did not affect blood biochemistry.This trial was registered at clinicaltrials.gov as NCT03656367.

Normal plasma apoB48 despite the virtual absence of apoB100 in a compound heterozygote with novel mutations in the MTTP gene.

"Normotriglyceridemic abetalipoproteinemia (ABL)" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies identified mutations in APOB gene which encoded truncated apoB longer than apoB48. Therefore, "Normotriglyceridemic ABL" can be a subtype of homozygous familial hypobetalipoproteinemia. Here, we report an atypical female case of ABL who was initially diagnosed with "normotriglyceridemic ABL", because she had normal plasma apoB48 despite the virtual absence of apoB100 and low plasma TG level. Next generation sequencing revealed that she was a compound heterozygote of two novel MTTP mutations: nonsense (p.Q272X) and missense (p.G709R). We speculate that p.G709R might confer residual triglyceride transfer activity of MTTP preferentially in the intestinal epithelium to the hepatocytes, allowing production of apoB48. Together, "normotriglyceridemic ABL" may be a heterogenous disorder which is caused by specific mutations in either APOB or MTTP gene.

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

ApoB-lipoprotein remnant dyslipidemia and high-fat meal intolerance is associated with markers of cardiometabolic risk in youth with obesity.

INTRODUCTION: Cardiovascular disease (CVD) originates in childhood and risk is exacerbated in obesity. Mechanisms of the etiologic link between early adiposity and CVD-risk remain unclear. Postprandial or non-fasting dyslipidemia is characterized by elevated plasma triglycerides (TG) and intestinal-apolipoprotein(apo)B48-remnants following a high-fat meal and is a known CVD-risk factor in adults. The aim of this study was to determine (a) whether the fasting concentration of apoB48-remnants can predict impaired non-fasting apoB48-lipoprotein metabolism (fat intolerance) and (b) the relationship of these biomarkers with cardiometabolic risk factors in youth with or without obesity. METHODS: We assessed fasting and non-fasting lipids in youth without obesity (n = 22, 10 males, 12 females) and youth with obesity (n = 13, 5 males, 8 females) with a mean BMI Z-score of 0.19 ± 0.70 and 2.25 ± 0.31 (P = .04), respectively. RESULTS: Fasting and non-fasting apoB48-remnants were elevated in youth with obesity compared to youth without obesity (apoB48: 18.04 ± 1.96 vs 8.09 ± 0.59, P < .0001, and apoB48AUC : 173.0 ± 20.86 vs 61.99 ± 3.44, P < .001). Furthermore, fasting plasma apoB48-remnants were positively correlated with the non-fasting response in apoB48AUC (r = 0.84, P < .0001) as well as other cardiometabolic risk factors including HOMA-IR (r = 0.61, P < .001) and leptin (r = 0.56, P < .0001). CONCLUSION: Fasting apoB48-remnants are elevated in youth with obesity and predict apoB48 postprandial dyslipidemia. ApoB48-remnants are associated with the extent of fat intolerance and appear to be potential biomarker of CVD-risk in youth.

Dietary saturated fats and apolipoprotein B48 levels are similarly associated with cognitive decline in healthy older aged Australians.

BACKGROUND AND OBJECTIVES: As the incidence and prevalence of Alzheimer's disease increases, so does the body of epidemiological and clinical research that suggests a relationship between dietary fatty acids, in particular saturates, and cognitive decline. In this study, we investigated the association between serum apolipoprotein B48 (apoB48), saturated fatty acid intake and consumption behaviour, and cognitive performance, in healthy, older aged Australians. METHODS AND STUDY DESIGN: We retrospectively analysed fasted serum apoB48 concentrations, food frequency questionnaire, and cognitive performance data collected from 147 participants (98F|49M) over the age of 50. We used Spearman's correlations and a nested domain model to evaluate the relationship between serum apoB48, dietary behaviour and measures of cognitive performance. RESULTS: Overall, we found that higher fasted apoB48 concentrations, and/or dietary behaviours which led to increased dietary consumption of diets high in saturated fatty acids, were inversely associated with cognition. Interestingly however, dietary behaviour patterns of saturated fatty acid consumption and serum apoB48 were linked with better secondary memory and perceptual speed, respectively. CONCLUSIONS: This is the first time that fasted apoB48 has been implicated as a biomarker for cognitive decline and Alzheimer's disease risk.

ApoB48-remnant lipoproteins are associated with increased cardiometabolic risk in adolescents.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) begins in youth, and is exacerbated by obesity and metabolic syndrome. Apolipoprotein (Apo)B-remnant cholesterol is considered a primary contributor to CVD risk. Fasting plasma apoB48 can be used as a biomarker of intestinal remnant cholesterol as well as postprandial dyslipidemia. In adults, elevated fasting plasma apoB48 strongly associates with cardiometabolic risk factors and obesity, whereas in adolescents there is limited data. The aim of this study was to measure fasting plasma apoB48 and determine the relationship with cardiometabolic risk factors in adolescents. METHODS: This is a cross-sectional study of fasting plasma apoB48 from the Western Australian Pregnancy Cohort (Raine) Study. Subjects were adolescent males and females aged 17 years with complete fasting plasma apoB48, biochemical, and anthropometry data (n = 1045). The relationship between fasting plasma apoB48 and other cardiometabolic risk factors was determined. The high-risk metabolic cluster variable was defined using elevated BMI, HOMA-IR, fasting plasma triglycerides, and systolic blood pressure. RESULTS: Fasting plasma apoB48 was significantly higher in male (15.28 ± 2.95 µg/mL) compared to female (12.45 ± 2.43 µg/mL) adolescents (p = 0.0003), and was increased by 21% (3.60 µg/mL; p = 0.0000) in the high-risk metabolic cluster group and more pronounced in males (31%, 6.15 µg/mL; p = 0.0000). Fasting plasma apoB48 was positively associated with fasting plasma triglycerides, total-cholesterol (but not LDL-C), insulin, leptin, HOMA-IR, and the anthropometric parameters, waist-circumference and skinfold-thickness. Fasting plasma apoB48 was inversely associated with fasting plasma HDL-C, and adiponectin. CONCLUSIONS: Plasma apoB48 remnant lipoproteins associate with cardiometabolic risk factors in adolescents and provide support for the screening of remnant cholesterol in youth.

Postprandial hyperlipidemia as a risk factor in patients with type 2 diabetes.

Introduction: Postprandial hyperlipidemia is a common feature of the atherogenic dyslipidemia in patients with type 2 diabetes. Quantification of this with oral fat tolerance tests is not used routinely in clinical practice and abnormal postprandial lipids are usually inferred from non-fasting plasma triglyceride levels. Identifying excessive postprandial hyperlipidemia may help to refine cardiovascular risk assessment but there are no treatments currently available which selectively target postprandial lipids and no large cardiovascular outcome trials using this as the entry criterion.Areas covered: In this review of relevant published material, we summarize the findings from the most important publications in this area.Expert opinion: Postprandial hyperlipidemia appears to contribute to the cardiovascular risk in patients with diabetes. Non-fasting triglyceride levels provide a surrogate marker of postprandial hyperlipidemia but more specific markers such as apoB48 levels may prove to be more reliable. Omega-3 fatty acids, fibrates and ezetimibe can reduce postprandial lipids but may not correct them completely. Several novel treatments have been developed to target hypertriglyceridemia and some of these may be particularly effective in improving postprandial levels. Further clinical trials are needed to establish the role of postprandial lipids in assessment of cardiovascular risk and to identify the most effective treatments.

Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial.

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

Effects of gastric bypass surgery on postprandial gut and systemic lipid handling.

BACKGROUND & OBJECTIVES: Obesity is often associated with increased postprandial triglyceride (TG) concentrations, mainly from chylomicrons- and VLDL-TG. These alterations are usually reverted to normal after gastric bypass surgery (GB), through mechanisms which remain unknown. The objective of this study was therefore to assess the contribution of exogenous labelled fatty acids ingested with a meal to postprandial blood chylomicrons and VLDL-TG concentrations after GB. SUBJECTS/METHODS: 7 GB patients 3-5 years after surgery (GB: 2M/5F, mean BMI 30 ± 2 kg/m2, mean age 40 ± 3 years), 6 overweight non operated subjects (OW: 1M/5F, mean BMI 31 ± 3 kg/m2, mean age 38 ± 2 years) and 8 normal weight healthy subjects (NW: 4M/4F, mean BMI 22 ± 1 kg/m2, mean age 26 ± 4 years) were studied over 7 h following ingestion of a liquid meal containing 18 g fat labelled with 250 mg 13C16 palmitate, 22 g protein, 36 g fructose and 36 g glucose. TG, 13C palmitate (13C-palm) and apoB48 concentrations were measured hourly in whole plasma and/or in chylomicrons and VLDL lipoprotein sub-fractions. RESULTS: OW subjects had higher chylomicron-than NW (chylo-TG 96.5 (23.1) vs 28.8 (11.8) mmol/l*420min (p = 0.02)), but similar total, chylo-13C-palm and apoB48 iAUCs. In GB, chylo- 13C-palm and apoB48 increased earlier after meal ingestion, but then remained lower than in NW and OW throughout the postprandial period. GB also had lower chylo-TG iAUCs than OW (8.9 (11.5) vs 96.5 (23.2) mmol/l*420min, p = 0.003). Their apoB48 iAUCs were not different from NW and OW (509.2 (90.5) vs 710.2 (80.5) and 870.1 (297.6) pg/ml*420min, all p > 0.05). CONCLUSIONS: An accelerated postprandial apoB48 rise, together with unchanged postprandial apoB48 iUAC, suggests that intestinal fat absorption and chylomicron secretion was quantitatively unaltered, but accelerated after gastric bypass. In contrast, the decreased postprandial chylo-TG and 13C-palm iAUCs suggest that plasma chylomicron clearance was enhanced after gastric bypass.

Acute whole apple consumption did not influence postprandial lipaemia: a randomised crossover trial.

Whole apples are a source of pectin and polyphenols, both of which show potential to modulate postprandial lipaemia (PPL). The present study aimed to explore the effects of whole apple consumption on PPL, as a risk factor for CVD, in generally healthy but overweight and obese adults. A randomised, crossover acute meal trial was conducted with seventeen women and nine men (mean BMI of 34·1 (sem 0·2) kg/m2). Blood samples were collected for 6 h after participants consumed an oral fat tolerance test meal that provided 1 g fat/kg body weight and 1500 mg acetaminophen per meal for estimating gastric emptying, with and without three whole raw Gala apples (approximately 200 g). Plasma TAG (with peak postprandial concentration as the primary outcome), apoB48, chylomicron-rich fraction particle size and fatty acid composition, glucose, insulin and acetaminophen were analysed. Differences between with and without apples were identified by ANCOVA. Apple consumption did not alter postprandial TAG response, chylomicron properties, glucose or acetaminophen (P > 0·05), but did lead to a higher apoB48 peak concentration and exaggerated insulin between 20 and 180 min (P < 0·05). Overall, as a complex food matrix, apples did not modulate postprandial TAG when consumed with a high-fat meal in overweight and obese adults, but did stimulate insulin secretion, potentially contributing to an increased TAG-rich lipoprotein production.

Correlates of pentraxin 3 serum concentration in men and women with type 2 diabetes.

Elevated levels of plasma pentraxin 3 (PTX3), a marker of inflammation, are associated with the risk of developing cardiovascular diseases in the general population, as well as in patients with type 2 diabetes (DM2). In this study, we aimed to determine factors associated with PTX3 serum concentrations in men and women with DM2. The study included 116 consecutive patients (67 men and 49 women) with DM2 from an outpatient diabetic clinic. Men were characterised by lower age and higher uric acid, creatinine and bilirubin concentrations and waist/hip ratio than women. In women, low-density lipoprotein cholesterol (LDL-C) levels were higher than in men. In men, median (interquartile range) values of PTX3 concentration were 4.02 (1.99), and in women they were 4.53 (3.31) ng/ml (NS). In men, PTX3 concentrations correlated with total cholesterol (TC), triglycerides, apolipoprotein (Apo) C3, Apo B48, Glc and creatinine levels. In women, PTX3 correlated significantly with TC and LDL-C and Apo B100. Partial regression analysis revealed that after adjusting for age, PTX3 concentrations in men were significantly associated with TC, LDL-C, triglycerides, creatinine, Apo C3 and Apo B48, while in women they were associated with TC, LDL-C and Apo B100. The results could be of importance in sex-specific prevention of vascular complications in DM2 patients.

Normal serum ApoB48 and red cells vitamin E concentrations after supplementation in a novel compound heterozygous case of abetalipoproteinemia.

BACKGROUND AND AIMS: Abetalipoproteinemia (ABL) is a rare recessive monogenic disease due to MTTP (microsomal triglyceride transfer protein) mutations leading to the absence of plasma apoB-containing lipoproteins. Here we characterize a new ABL case with usual clinical phenotype, hypocholesterolemia, hypotriglyceridemia but normal serum apolipoprotein B48 (apoB48) and red blood cell vitamin E concentrations. METHODS: Histology and MTP activity measurements were performed on intestinal biopsies. Mutations in MTTP were identified by Sanger sequencing, quantitative digital droplet and long-range PCR. Functional consequences of the variants were studied in vitro using a minigene splicing assay, measurement of MTP activity and apoB48 secretion. RESULTS: Intestinal steatosis and the absence of measurable lipid transfer activity in intestinal protein extract supported the diagnosis of ABL. A novel MTTP c.1868G>T variant inherited from the patient's father was identified. This variant gives rise to three mRNA transcripts: one normally spliced, found at a low frequency in intestinal biopsy, carrying the p.(Arg623Leu) missense variant, producing in vitro 65% of normal MTP activity and apoB48 secretion, and two abnormally spliced transcripts resulting in a non-functional MTP protein. Digital droplet PCR and long-range sequencing revealed a previously described c.1067+1217_1141del allele inherited from the mother, removing exon 10. Thus, the patient is compound heterozygous for two dysfunctional MTTP alleles. The p.(Arg623Leu) variant may maintain residual secretion of apoB48. CONCLUSIONS: Complex cases of primary dyslipidemia require the use of a cascade of different methodologies to establish the diagnosis in patients with non-classical biological phenotypes and provide better knowledge on the regulation of lipid metabolism.

Polymorphisms rs2167444 and rs508384 in the SCD1 Gene Are Linked with High ApoB-48 Levels and Adverse Profile of Cardiometabolic Risk Factors.

Elevated plasma concentration of apolipoprotein B-48 (apoB-48) is an independent risk factor of cardiovascular disease. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipogenic enzyme and a key regulator of fuel metabolism. The aim of this study was to analyse associations between clinical, biochemical, and genetic factors and different apoB-48 levels in subjects at increased cardiometabolic risk. We examined 220 subjects exhibiting at least one metabolic syndrome (MetS) component. In conjunction with basic clinical, anthropometric and laboratory measurements, we analysed various polymorphisms of stearoyl-CoA desaturase-1 (SCD1). Subjects were divided into two groups according to the median apoB-48 level: (1) high apoB-48 (≥ 7.9 mg/l, N = 112) and (2) low apoB-48 (< 7.9 mg/l, N = 108). Neither group differed significantly in anthropometric measures. High plasma apoB-48 levels were associated with increased systolic blood pressure (+3 %; P < 0.05), MetS prevalence (59.8 vs. 32.4 %; P < 0.001), small-dense LDL frequency (46.4 vs. 20.4 %; P < 0.001), triglycerides (+97 %; P < 0.001), non-HDLcholesterol (+27 %; P < 0.001), and lower concentrations of HDL-cholesterol (-11 %; P < 0.01). This group was further characterized by a higher HOMA-IR index (+54 %; P < 0.001) and increased concentrations of conjugated dienes (+11 %; P < 0.001) and oxidatively modified LDL (+ 38 %; P < 0.05). Lower frequencies of SCD1 minor genotypes (rs2167444, rs508384, P < 0.05) were observed in subjects with elevated plasma concentrations of apoB-48. Elevated plasma concentrations of apoB-48 are associated with an adverse lipid profile, higher systolic blood pressure, insulin resistance, and oxidative stress. Lower proportions of minor SCD1 genotypes (rs2167444, rs508384) implicate the role of genetic factors in the pathogenesis of elevated levels of apoB-48.

A pre-meal of whey proteins induces differential effects on glucose and lipid metabolism in subjects with the metabolic syndrome: a randomised cross-over trial.

PURPOSE: Postprandial lipaemia (PPL), an independent risk factor for cardiovascular disease, is affected by composition and timing of meals. We evaluated if whey proteins (WP) consumed as a pre-meal before a fat-rich meal reduce postprandial triglyceride (TG) and apolipoprotein B-48 (ApoB-48) responses in subjects with the metabolic syndrome (MeS). METHODS: An acute, randomised, cross-over trial was conducted. 20 subjects with MeS consumed a pre-meal of 0, 10 or 20 g WP 15 min prior to a fat-rich meal. The responses of TG and ApoB-48 were assessed. We also analysed postprandial responses of free fatty acids (FFA), glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and paracetamol (reflecting gastric emptying rates). RESULTS: WP pre-meal did not alter the TG or ApoB-48 responses. In contrast, the insulin response was more pronounced after a pre-meal of 20 g WP than with 10 g WP (P = 0.0005) and placebo (P < 0.0001). Likewise, the postprandial glucagon response was greater with a pre-meal of 20 g WP than with 10 g WP (P < 0.0001) and 0 g WP (P < 0.0001). A pre-meal with 20 g of WP generated lower glucose (P = 0.0148) and S-paracetamol responses (P = 0.0003) and a higher GLP-1 response (P = 0.0086) than placebo. However, the pre-meal did not influence responses of GIP, FFA or appetite assessed by a Visual Analog Scale. CONCLUSIONS: Consumption of a WP pre-meal prior to a fat-rich meal did not affect TG and chylomicron responses. In contrast, the WP pre-meal stimulates insulin and glucagon secretion and reduces blood glucose as expected, and delays gastric emptying. Consequently, our study points to a differential impact of a WP pre-meal on lipid and glucose metabolism to a fat-rich meal in subjects with MeS.

Hypothesis II: The majority of VLDL-apoB48 remnants in postprandial plasma are derived from the liver, not from the intestine.

We have long thought that remnant lipoproteins (RLP) in the postprandial plasma contain CM remnants (exogenous remnants; RLP-apoB48) and VLDL remnants (endogenous remnants; RLP-apoB100) of different origin, i.e. produced in the intestine and liver, respectively. However, the majority of CM remnants incorporated into liver from the circulation are degraded in liver and may be reused for the remodeling of VLDL. Namely, the most of the apoB48 in CM remnants are smoothly incorporated into the liver after fat intake along with lipids and other apolipoproteins via the LDL receptor and LDL-receptor-related protein (LRP). Subsequently, apoB48 may be reconstituted in VLDL as VLDL apoB48 through an essential physiological pathway similar or the same to that of VLDL apoB100 formation in the liver and secreted into the circulation as VLDL apoB48 to form their remnants. Because those particles are newly reconstituted in liver as a portion of VLDL, we propose that both RLP-apoB100 and RLP-apoB48 are endogenous VLDL remnants produced in liver after fat intake. Also we predict the presence of a new pathway for the formation of VLDL apoB48 along with VLDL apoB100 in liver in humans similar in mice and rats.

A pilot study of the effect of ezetimibe for postprandial hyperlipidemia.

This study aimed to explore the feasible effect of ezetimibe for postprandial hyperlipidemia (PPHP).Sixty participants were included in this study. Of these, 30 subjects in the intervention group received ezetimibe, while the remaining 30 participants in the control group did not undergo ezetimibe. All patients in intervention group were treated for a total of 2 weeks. Primary endpoints consisted of serum levels of total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). Secondary endpoints included apoB-48, remnant lipoprotein cholesterol (RLP-C), blood glucose, insulin, hemoglobin A1c (HbA1c), and monocyte chemotactic protein (MCP). All outcomes were measured before and after 2-week treatment.After 2-week treatment, participants in the intervention group did not show better outcomes in primary endpoints of Total-C, LDL-C, HDL-C, and TG; and secondary endpoints of apoB-48, RLP-C, blood glucose, insulin, HbA1c, and MCP, compared with subjects in the control group.The results of this study showed that ezetimibe may be not efficacious for participants with PPHP after 2-week treatment.

Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Liraglutide Reduces Postprandial Hyperlipidemia by Increasing ApoB48 (Apolipoprotein B48) Catabolism and by Reducing ApoB48 Production in Patients With Type 2 Diabetes Mellitus.

Objective- Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). Approach and Results- We performed an in vivo kinetic study with stable isotopes (D8-valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1.2 mg/d). We also evaluated, in mice, the effect of a 1-week liraglutide treatment on postload triglycerides and analysed in vitro on jejunum, the direct effect of liraglutide on the expression of genes involved in the biosynthesis of chylomicron. In diabetic patients, liraglutide treatment induced a dramatic reduction of ApoB48 pool (65±38 versus 162±87 mg; P=0.005) because of a significant decrease in ApoB48 production rate (3.02±1.33 versus 6.14±4.27 mg kg-1 d-1; P=0.009) and a significant increase in ApoB48 fractional catabolic rate (5.12±1.35 versus 3.69±0.75 pool d-1; P=0.005). One-week treatment with liraglutide significantly reduced postload plasma triglycerides in mice and liraglutide, in vitro, reduced the expression of ApoB48, DGAT1 (diacylglycerol O-acyltransferase 1), and MTP (microsomal transfer protein) genes. Conclusions- We show that treatment with liraglutide induces a significant reduction of the ApoB48 pool because of both a reduction of ApoB48 production and an increase in ApoB48 catabolism. In vitro, liraglutide reduces the expression of genes involved in chylomicron synthesis. These effects might benefit cardiovascular health. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02721888.

Postprandial Hyperchylomicronemia and Thin-Cap Fibroatheroma in Nonculprit Lesions.

Objective- Although postprandial hypertriglyceridemia can be a risk factor for coronary artery disease, the extent of its significance remains unknown. This study aimed to investigate the correlation between the postprandial lipid profiles rigorously estimated with the meal tolerance test and the presence of lipid-rich plaque, such as thin-cap fibroatheroma (TCFA), in the nonculprit lesion. Approach and Results- A total of 30 patients with stable coronary artery disease who underwent a multivessel examination using optical coherence tomography during catheter intervention for the culprit lesion were enrolled. Patients were divided into 2 groups: patients with TCFA (fibrous cap thickness ≤65 µm) in the nonculprit lesion and those without TCFA. Serum remnant-like particle-cholesterol and ApoB-48 (apolipoprotein B-48) levels were measured during the meal tolerance test. The value of remnant-like particle-cholesterol was significantly greater in the TCFA group than in the non-TCFA group ( P=0.045). Although the baseline ApoB-48 level was similar, the increase in the ApoB-48 level was significantly higher in the TCFA group than in the non-TCFA group ( P=0.028). In addition, the baseline apolipoprotein C-III levels was significantly greater in the TCFA group ( P=0.003). These indexes were independent predictors of the presence of TCFA (ΔApoB-48: odds ratio, 1.608; 95% confidence interval, 1.040-2.486; P=0.032; apolipoprotein C-III: odds ratio, 2.581; 95% confidence interval, 1.177-5.661; P=0.018). Conclusions- Postprandial hyperchylomicronemia correlates with the presence of TCFA in the nonculprit lesion and may be a residual risk factor for coronary artery disease.