Postprandial Triglyceride-rich Lipoproteins Research Articles

Postprandial Triglyceride-Rich Lipoproteins-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Inflammation in White Adipocytes

BackgroundObesity and postprandial hypertriglyceridemia, characterized by an increase in triglyceride-rich lipoproteins (TRLs), cause chronic low-grade inflammation. It is unclear how postprandial TRLs affect inflammation in white adipocytes. ObjectivesThe objectives of the study were to explore the inflammatory response of postprandial TRLs in white adipocytes and investigate the possible mechanism. MethodsWe measured postprandial triglyceride (TG) and high-sensitivity C-reactive protein (hsCRP) concentrations in 204 recruited subjects and treated white adipocytes from mice with postprandial TRLs from above patients with hypertriglyceridemia. ResultsSerum hsCRP concentrations and BMI were positively related to TG concentrations in the postprandial state. Postprandial TRLs increased mRNA and protein expression of inflammatory factors, including interleukin-1β, via the NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway, and impaired autophagy flux in white adipocytes of mice. TRLs also induced lysosomal damage as evidenced by the reduced protein expression of lysosome-associated membrane proteins-1 and Cathepsin L. Inhibition of Cathepsin B, NLRP3, and mTOR signaling improved autophagy/lysosome dysfunction and inhibited the activation of the NLRP3/Caspase-1 pathway and inflammatory factors induced by TRLs in white adipocytes. ConclusionsOur results suggest that postprandial hypertriglyceridemia causes chronic inflammation in adipocytes through TRL-induced lysosomal dysfunction and impaired autophagic flux in an mTOR-dependent manner.

Garcinia cambogia Extract Increased Hepatic Levels of Lipolysis-Stimulated Lipoprotein Receptor and Lipids in Mice on Normal Diet.

Garcinia cambogia extract (GCE) is a popular weight-loss supplement that also lowers plasma triglyceride (TG) levels. We hypothesized that GCE-mediated inhibition of ATP citrate lyase and thereby hepatic TG production could lead to compensatory mechanisms, including increased hepatic TG uptake via lipoprotein receptors. GCE (20 mg/day) administered 40 days orally to female C57BL/6Rj mice on a standard chow diet led to a decrease in both plasma fasting and post-prandial TG-rich lipoprotein levels, but with no significant change in body weight gain. Lipolysis stimulated lipoprotein receptor (LSR) protein levels, but not those of LDL-receptor, were increased as compared to controls. Mouse Hepa1-6 cells treated with the GCE active ingredient, hydroxycitrate, also led to increased LSR protein levels. Hepatic total cholesterol, TG, and muscle TG contents were higher in GCE-treated animals as compared to controls, whereas adipose TG levels were unchanged. LSR and LDL-receptor protein levels were correlated with liver total cholesterol, but only LDL-receptor was associated with liver TG. These results show that GCE treatment in mice on a standard chow diet led to significantly increased liver and muscle lipids, with no significant change in adipose tissue TG levels, which should be considered in the long-term use of GCE.

The early effects of sleeve gastrectomy on postprandial chylomicron triglycerides during the progression of type 2 diabetes

BackgroundIt remains unclear whether early sleeve gastrectomy (SG) improves postprandial very-low-density lipoprotein (VLDL) as well as chylomicron triglycerides (TGs) in a weight-independent manner in patients with or without type 2 diabetes (DM). Herein we investigated the early effects of SG on postprandial VLDL and chylomicron kinetics. MethodsA liquid meal test was performed before and after 1 week of SG. The plasma was collected for postprandial triglyceride-rich lipoprotein kinetics analyses, including VLDLs and chylomicrons, isolated by high-speed ultracentrifugation. Lipidomics and metabolomics were used to profile lipid and metabolite compositions of plasma and postprandial chylomicrons. De novo fatty acid synthesis in intestinal epithelial cells treated with chylomicron metabolites was examined using RT-PCR, immunoblotting, and free fatty acid measurement. ResultsWe found that patients with DM had markedly higher VLDL TGs than patients without DM, and such an increase was still retained after SG. In contrast, SG significantly decreased postprandial chylomicron TGs, but surprisingly, the degree of the reduction in patients with DM was less prominent than in patients without DM, confirmed by untargeted lipidomics analysis. Moreover, 5 unique metabolites potentially linked to de novo fatty acid synthesis from the pathway analysis were discovered by further metabolomic analysis of postprandial chylomicrons from patients with DM who underwent SG and verified by In vitro intestinal epithelial cell culture experiments. ConclusionsSG in 1 week did not impact postprandial VLDL but decreased chylomicron TGs. Patients with DM keep higher postprandial chylomicron TG concentrations than patients without it after SG, potentially through some unique metabolites that increase intestinal fatty acid synthesis. These results implicate the timing for SG to reach lower intestinal fatty acid synthesis and postprandial chylomicron TG production is prior to the diagnosis of DM to potentially reduce cardiovascular risks.

Elevated postprandial triglyceride-rich lipoproteins in patients with diabetes and stable coronary artery disease correlated with early renal damage and systemic inflammation

BackgroundDyslipidaemia is key in the development of coronary heart disease (CHD) in patients with diabetes mellitus (DM). Accumulated evidence supports that diabetic nephropathy increases the mortality risk of patients with CHD, while the influence of diabetic dyslipidaemia on renal damage in patients with DM and CHD remains unknown. Moreover, recent data indicate that postprandial dyslipidaemia has predictive value in terms of CHD prognosis, especially in patients with DM. The study aimed to determine the relationship of triglyceride-rich lipoproteins (TRLs) after daily Chinese breakfast on systemic inflammation and early renal damage in Chinese patients with DM and SCAD.MethodsPatients with DM diagnosed with SCAD while in the Department of Cardiology of Shengjing Hospital from September 2016 to February 2017 were enrolled in this study. Fasting and 4-h postprandial blood lipids, fasting blood glucose, glycated haemoglobin, urinary albumin-to-creatinine ratio (UACR), serum interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) concentrations, and other parameters were measured. Fasting and postprandial blood lipid profiles and inflammatory cytokines were analysed using a paired t-test. The association between variables was analysed using Pearson or Spearman bivariate analysis. P < 0.05 was considered to be statistically significant.ResultsThe study enrolled 44 patients in total. Compared with fasting state, postprandial total cholesterol high-density lipoprotein-cholesterol (HDL-C),low-density lipoprotein-cholesterol (LDL-C) and non-high-density lipoprotein-cholesterol (non-HDL-C) all showed no significant change. Postprandial serum triglyceride (TG) concentration increased significantly compared with that at fasting (1.40 ± 0.40 vs. 2.10 ± 0.94 mmol/L, P < 0.001), as did serum remnant lipoprotein-cholesterol (RLP-C) (0.54 ± 0.18 mmol/L vs. 0.64 ± 0.25 mmol/L). Pearson analysis revealed that serum TG and RLP-C positively correlated before and after breakfast. Moreover, during fasting, positive correlations were observed between TG and serum IL-6, TNF-α, and UACR. Positive correlations were observed between RLP-C and IL-6, UACR under fasting condition, while both TG and RLP-C were positively correlated with postprandial serum IL-6, TNF-α, and UACR concentrations. Finally, positive correlations were observed between UACR and IL-6 and TNF-α concentration under both fasting and postprandial conditions.ConclusionsAn increase in postprandial TRLs was observed in Chinese patients with DM and SCAD after daily breakfast, and this increase may be related to early renal injury via the induction of systemic inflammation.

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.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Postprandial triglyceride-rich lipoproteins promote the adipogenic differentiation of adipose-derived mesenchymal stem cells via the LRP1/caveolin-1/AKT1 pathway

Diet-induced obesity (OB) is usually accompanied by hypertriglyceridemia, which is characterized by the accumulation of triglyceride (TG)-rich lipoprotein (TRL) particles in the circulation. We previously found that postprandial TRL combined with insulin induced the adipogenic differentiation of 3T3-L1 preadipocytes, which may represent a key mechanism underlying obesity. However, the specific mechanism and signaling pathway involved in this process remain to be fully elucidated. In this study, we found that, in the postprandial state, patients with obesity had significantly higher levels of TG and remnant cholesterol (RC) than normal-weight controls. In vitro, we found that postprandial TRL, together with insulin, promoted the adipogenic differentiation of adipose-derived mesenchymal stem cells (AMSCs), as evidenced by the increased expression of lipogenesis-related genes and their protein products, including low-density lipoprotein related protein 1 (LRP1). Besides, caveolin-1 (Cav-1) expression was also significantly upregulated under this condition. Cav-1 and LRP1 were observed to interact, and then led to the activation of the PI3K/AKT1 signaling pathway. Meanwhile, the inhibition of LRP1 or Cav-1 significantly attenuated the adipogenic differentiation of AMSCs and downregulated AKT1 phosphorylation levels. Moreover, treatment with a selective AKT1 inhibitor significantly suppressed postprandial TRL and insulin-induced adipogenesis in AMSCs. Combined, our results demonstrated that, in association with insulin, postprandial TRL can promote the adipogenic differentiation of AMSCs in a manner that is dependent on the LRP1/Cav-1-mediated activation of the PI3K/AKT1 signaling pathway. Our findings indicated that a postprandial increase in TRL content is a critical factor in the pathogenesis of hypertriglyceridemia and diet-induced obesity.

Response of lipoproteins to a meal tolerance test in patients with type 2 diabetes and hypertriglyceridemia

Background and Aims : High fasting TG is a marker of increased postprandial TG-rich lipoproteins and their remnants. Non-fasting TG is said to be 20-25% higher than fasting TG. It remains unclear what determines the non-fasting lipid profile. The aim of this study was to examine lipid parameters in fasting and postprandial states and to explore their relationship in patients with type 2 diabetes (T2D) and hypertriglyceridemia.Methods: This was a post-hoc analysis of a pemafibrate phase 3 clinical trial in Japanese patients with T2D and hypertriglyceridemia who underwent a meal tolerance test (N=68). Baseline data before starting the study drug were analyzed. The blood sampling was conducted at 0, 1, 2, 4.5 and 6.5 h after taking the test meal (592 kcal).Results: After taking the test meal, TG increased from 256.8 mg/dL (0 h) to 274.8 mg/dL (1 h, +11.0%), 330.8 mg/dL (2 h, +36.3%), 341.8 mg/dL (4.5 h, +42.1%) and 285.8 mg/dL (6.5 h, +19.7%). The postprandial apoB48 time course was similar to that of TG, whereas the increase in RemL-C was slower. AUC0-6.5h-TG and AUC0-6.5h-RemL-C were significantly associated with baseline values for TG, RemL-C, apoB48, apoC2, apoC3 and apoE.Conclusions: In patients with T2D and hypertriglyceridemia, plasma TG levels increased up to approximately 1.5-fold after taking the test meal. Postprandial TG and RemL-C increases can be predictable from the baseline values for TG, RemL-C, apoB48, apoC2, apoC3 and apoE. Background and Aims : High fasting TG is a marker of increased postprandial TG-rich lipoproteins and their remnants. Non-fasting TG is said to be 20-25% higher than fasting TG. It remains unclear what determines the non-fasting lipid profile. The aim of this study was to examine lipid parameters in fasting and postprandial states and to explore their relationship in patients with type 2 diabetes (T2D) and hypertriglyceridemia. Methods: This was a post-hoc analysis of a pemafibrate phase 3 clinical trial in Japanese patients with T2D and hypertriglyceridemia who underwent a meal tolerance test (N=68). Baseline data before starting the study drug were analyzed. The blood sampling was conducted at 0, 1, 2, 4.5 and 6.5 h after taking the test meal (592 kcal). Results: After taking the test meal, TG increased from 256.8 mg/dL (0 h) to 274.8 mg/dL (1 h, +11.0%), 330.8 mg/dL (2 h, +36.3%), 341.8 mg/dL (4.5 h, +42.1%) and 285.8 mg/dL (6.5 h, +19.7%). The postprandial apoB48 time course was similar to that of TG, whereas the increase in RemL-C was slower. AUC0-6.5h-TG and AUC0-6.5h-RemL-C were significantly associated with baseline values for TG, RemL-C, apoB48, apoC2, apoC3 and apoE. Conclusions: In patients with T2D and hypertriglyceridemia, plasma TG levels increased up to approximately 1.5-fold after taking the test meal. Postprandial TG and RemL-C increases can be predictable from the baseline values for TG, RemL-C, apoB48, apoC2, apoC3 and apoE.

A meal rich in palm oil or butter modifies the sphingolipid profile of postprandial triglyceride-rich lipoproteins from type 2 diabetic women

Elevated concentrations of triglyceride-rich lipoproteins (TGRL) in the fasting and postprandial states are risk factors for cardiovascular events, especially in type 2 diabetes (T2D). T2D modifies the lipid composition of plasma and lipoproteins and some sphingolipids (SP) have been validated as potent predictive biomarkers of cardiovascular disease occurrence. The main objectives of the present study were to characterize the plasma SP profile in fasting T2D patients and to determine whether SP are modified in postprandial TGRL from these patients compared to fasting TGRL. In a randomized parallel-group study, 30 T2D women ingested a breakfast including 20g lipids from either hazelnut cocoa palm oil-rich spread (Palm Nut) or Butter. Plasma was collected and TGRL were isolated by ultracentrifugation at fasting and 4h after the meal. Fasting samples of 6 control subjects from another cohort were analyzed for comparison. SP were analyzed by tandem mass spectrometry. Plasma from fasting T2D patients had higher ceramide (Cer) and ganglioside GM3 concentrations, and lower concentrations of sphingosylphosphorylcholine vs healthy subjects. In postprandial TGRL from T2D patients compared to those in the fasting state, Cer concentrations and especially C16:0, C24:1 and C24:0 molecular species, increased after the Palm Nut or Butter breakfast. A positive correlation was observed in the Palm Nut group between changes (Δ4h-fasting) of summed C16:0+C22:0+C24:1+C24:0 Cer concentrations in TGRL, and changes in plasma TG, TGRL-TG and TGRL-C16:0 concentrations. Altogether in T2D, the altered profile of plasma SP and the increased Cer concentrations in postprandial TGRL could contribute to the increased atherogenicity of TGRL.

ANGPTL3 Is Involved in the Post-prandial Response in Triglyceride-Rich Lipoproteins and HDL Components in Patients With Coronary Artery Disease.

It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.

A Meal Rich in Palm Oil or Butter Modifies the Sphingolipid Profile of Postprandial Triglyceride-Rich Lipoproteins From Type 2 Diabetic Patients

ObjectivesElevated concentrations of triglyceride-rich lipoproteins (TGRL) in the fasting and postprandial states are a risk factor for cardiovascular events in type 2 diabetes (T2D). Dyslipidemia in T2D is associated with modifications in the lipidome of plasma lipoproteins and some plasma sphingolipids (SP) have been validated as potent predictive biomarkers of cardiovascular disease occurrence. The objective of our clinical study was to determine whether sphingolipids (SP) are modified in postprandial triglyceride-rich lipoproteins (TGRL) from type 2 diabetic (T2D) patients as compared to fasting TGRL, following a saturated fatty meal. MethodsIn a randomized parallel-group study, 30 T2D women ingested a breakfast including 20 g lipids from either hazelnut cocoa palm oil-rich spread (Palm Nut) or butter. TGRL were isolated by ultracentrifugation at fasting and 4 hours after the ingested meal. SP classes and SP molecular species were analyzed by tandem mass spectrometry. ResultsCompared with plasma from healthy subjects, plasma from fasting T2D patients had higher ceramide (Cer, +34%) and ganglioside (GM3, +28%) concentrations, and lower concentrations of sphingosylphosphorylcholine (-66%). In postprandial TGRL compared to fasting TGRL from T2D patients, total Cer concentrations and especially C16:0, C24:1 and C24:0 molecular species, increased after the Palm Nut (+45%) or Butter (+40%) breakfast. A positive correlation was observed in the Palm Nut group between changes (D 4 h postprandial-fasting) of summed C16:0 + C22:0 + C24:1 + C24:0 Cer concentrations in TGRL, and changes in plasma TG, TGRL TG as well as TGRL C16:0 concentrations. ConclusionsThe ingestion of a single fat-rich meal from a vegetable or dairy source by T2D patients led to increased concentrations of Cer in postprandial TGRL and could contribute to the increased atherogenicity of TGRL in T2D. Funding SourcesThis work was supported by Inserm.

477-P: Vagal GLP-1–Mediated Reductions in Postprandial Lipids Are Sensitive to Fructose Feeding

Dyslipidemia is a common co-morbidity of insulin resistance, where chronic elevations in hepatic and intestinal lipoproteins are linked to cardiovascular disease. Postprandial production is regulated in-part by gut-derived hormones such as glucagon-like peptide (GLP) -1. Although degradation-resistant analogs of GLP-1 continue to work in diabetic individuals, none have examined whether GLP-1s endogenous neuroendocrine signalling pathways are affected by diet-induced dyslipidemia. Thus, we sought to test whether native GLP-1 could modulate postprandial lipids in a fructose-fed hamster model.Hamsters were fed either a chow or fructose-enriched (FF) diet for 14 days, then received a portal vein injection of either GLP-1 (7-36) or vehicle control to examine if they remained responsive to portal GLP-1. Separately, in hamsters fed either chow or a fat/fructose/cholesterol enriched (FFC) diet we performed nodose ganglia (NG) injections with GLP-1 (7-36) or vehicle. To recapitulate the loss of vagal GLP-1R signalling in the absence of dietary intervention we selectively deafferented GLP-1R containing NG neurons via injection of the cytotoxin saporin conjugated to exendin-4. After treatment, animals received a gavage of olive oil and an intraperitoneal injection of poloxamer to prevent lipoprotein clearance. Postprandial triglyceride-rich lipoproteins isolated via density ultracentrifugation were assessed via blood draws over a 6-hour period.Chow-fed hamsters saw significant reductions in post-prandial lipids after portal GLP-1 injection, whereas FF-fed hamsters were unaffected. Chow-fed hamsters were similarly responsive to GLP-1 (7-36) injection into the NG, displaying reduced postprandial lipids; however, FFC-fed hamsters showed no reduction in plasma lipids. Finally, selective deafferentation of NG GLP-1R-containing neurons caused significant rises in postprandial TG and TRL, underscoring the importance of GLP-1R insensitivity in states of metabolic disease. Disclosure S.S.Hoffman: None. D.C.Alvares: None. K.Adeli: None. Funding CIHR Foundation Grant

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).

Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia.

Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (Ldlr-/-), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.

Oleanolic Acid-Enriched Olive Oil Alleviates the Interleukin-6 Overproduction Induced by Postprandial Triglyceride-Rich Lipoproteins in THP-1 Macrophages

Oleanolic acid (OA), a triterpene that is highly present in olive leaves, has been proposed as a component of functional foods for the prevention of metabolic syndrome, due to its anti-inflammatory activity. We analyzed the effects of OA on inflammatory parameters and signaling proteins in LPS-stimulated THP-1 macrophages. Thus, THP-1 macrophages were incubated with LPS for 48 h after pretreatment with OA at different concentrations. Pretreatment with OA was significantly effective in attenuating IL-6 and TNF-α overproduction induced by LPS in macrophages, and also improved the levels of AMPK-α. We also evaluated the effects of human triglyceride-rich lipoproteins (TRLs) derived from individuals consuming an OA-enriched functional olive oil. For this purpose, TRLs were isolated from healthy adolescents before, 2 and 5 h postprandially after the intake of a meal containing the functional olive oil or common olive oil, and were incubated with THP-1 macrophages. THP-1 macrophages incubated with TRLs isolated at 2 h after the consumption of the OA-enriched olive oil showed significant lower levels of IL-6 compared to the TRLs derived from olive oil. Our results suggest that OA might have potential to be used as a lipid-based formulation in functional olive oils to prevent inflammatory processes underlying metabolic syndrome in adolescents.

Role of growth hormone in hepatic and intestinal triglyceride-rich lipoprotein metabolism

Elevated plasma concentrations of hepatic- and intestinally-derived triglyceride-rich lipoproteins (TRL) are implicated in the pathogenesis of atherosclerotic cardiovascular disease and all-cause mortality. Excess of TRL is the driving cause of atherogenic dyslipidemia commonly occurring in insulin-resistant individuals such as patients with obesity, type 2 diabetes and metabolic syndrome. Interestingly, growth hormone (GH)-deficient individuals display similar atherogenic dyslipidemia, suggesting an important role of GH and GH deficiency in the regulation of TRL metabolism. We aimed to examine the direct and/or indirect role of GH on TRL metabolism. We investigated the effect on fasting and postprandial hepatic-TRL and intestinal-TRL metabolism of short-term (one month) withdrawal of GH in 10 GH-deficient adults. After GH withdrawal, we found a reduction in fasting plasma TRL concentration (significant decrease in TRL-TG, TRL-cholesterol, TRL-apoB-100, TRL-apoC-III and TRL-apoC-II) but not in postprandial TRL response. This reduction was due to fewer fasting TRL particles without a change in TG per particle and was not accompanied by a change in postprandial TRL-apoB-48 response. Individual reductions in TRL correlated strongly with increases in insulin sensitivity and decreases in TRL-apoC-III. In this relatively short term 'loss of function' human experimental model, we have shown an unanticipated reduction of hepatic-TRL particles despite increase in total body fat mass and reduction in lean mass. These findings contrast with the atherogenic dyslipidemia previously described in chronic GH deficient states, providing a new perspective for the role of GH in lipoprotein metabolism.

Long-term effects of a short-term high-fat challenge on innate immune cell function in humans

Background and Aims: Triglyceride-rich lipoproteins (TRLs) are an independent risk factor for atherosclerotic cardiovascular disease (CVD). Monocyte-derived macrophages are regulators of the atherosclerotic process. We recently showed that monocytes can adopt a long-term pro-inflammatory phenotype upon brief stimulation with atherogenic stimuli, such as oxidized LDL. This is termed trained immunity. We hypothesized that a single high-fat challenge induces trained immunity, which could contribute to the atherogenic effects of transient postprandial TRL elevations.

Postprandial triglyceride-rich lipoproteins-induced premature senescence of adipose-derived mesenchymal stem cells via the SIRT1/p53/Ac-p53/p21 axis through oxidative mechanism

The accumulation of senescent adipose-derived mesenchymal stem cells (AMSCs) in subcutaneous white adipose tissue (WAT) is the main cause for the deterioration of WAT and the subsequent age-related disorders in obesity. The number of AMSCs staining positively for senescence-associated-β-galactosidase (SA-β-Gal) increased significantly after incubation with postprandial triglyceride-rich lipoproteins (TRL), accompanied by an impaired cell proliferation capacity and increased expression of inflammatory factors. Besides, the expression of anti-aging protein, silent mating-type information regulation 2 homolog 1 (SIRT1), was downregulated significantly, while those of acetylated p53 (Ac-p53), total p53, and p21 proteins were upregulated significantly during postprandial TRL-induced premature senescence of AMSCs. Furthermore, the production of intracellular reactive oxygen species (ROS) in the TRL group increased significantly, while pretreatment with the ROS scavenger N-acetyl-L-cysteine effectively attenuated the premature senescence of AMSCs by decreasing ROS production and upregulating SIRT1 level. Thus, postprandial TRL induced premature senescence of AMSCs through the SIRT1/p53/Ac-p53/p21 axis, partly through increased oxidative stress.

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.

Acute dietary saturated fat intake suppresses human monocyte subset inflammatory and chemokine responses

Abstract Background Dietary saturated fat (SF) intake is implicated in increasing cardiovascular risk. Studies suggest SF may incite an inflammatory immune response yet the mechanisms for this remain unclear. Circulating blood monocyte subsets (classical “CD16low” and non-classical/intermediate “CD16high”) are thought to differentially contribute to the macrophage foam cell burden in atherosclerotic plaque, yet they are heterogenous and much is still unknown about their response to dietary lipid. Purpose This dietary intervention study hypothesised that a subset-specific monocyte response occurs following acute SF intake in healthy individuals.Top of Form Methods 10 healthy participants were fed a coconut oil, lauric acid-rich meal. Monocyte subsets were purified from fasting and 4h postprandial blood by fluorescence activated cytometry (FACS) into CD16low and CD16high subsets. Surface marker expression was recorded by FACS, gene expression by qPCR, lipid loading by fluorescence microscopy, cytokine responses by ELISA and mass spectrometry was utilised to trace dietary fat into circulating monocytes. Triglyceride rich lipoprotein (TGRL) was obtained through ultracentrifugation of postprandial blood. TLR agonists LPS (TLR4) and R848 (TLR7/8) were used to replicate infectious stimuli to provoke a cytokine response. Results SF meal intake resulted in a 4h postprandial rise in serum triglycerides (TG). Other than a small rise in HLA-DR in postprandial CD16low monocytes, no changes in CD14, CD16 or CD11c levels were noted. Inflammatory gene expression was downregulated although a rise in lipid handling gene ABCA1 was noted in both subsets. Postprandial monocytes accumulated cytoplasmic neutral lipid droplets (larger and more numerate droplets in CD16low). Mass-spectrometry confirmed entry of dietary lipid into circulating monocytes. Postprandial monocyte functional responses were impaired; lipid-loaded postprandial monocytes were less able to migrate towards a chemokine gradient. Following TLR challenge, the inflammatory response was abrogated in postprandial monocytes, further suppressed by in vitro postprandial TGRL addition. Lipidomic analyses confirmed postprandial monocyte lauric acid accumulation in the form of free fatty acid and TG trilaurin, and 9(S)-, 13(S)-HODE and 17(S)-HDoHE, that are metabolites of docosahexanoic acid (DHA) and possess anti-inflammatory properties. The attached graphical abstract summarises the pertinent findings. Conclusions Acute dietary SF intake of a lauric acid-rich meal results in postprandial monocyte suppression of inflammatory TLR responses, a reduction in the ability to migrate towards a chemokine gradient whilst accumulating cytoplasmic neutral lipid droplets. The immunosuppression may be caused by accumulation of anti-inflammatory metabolites of DHA. Graphical Abstract Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, UK