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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?

ABSTRACT: We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n?-?3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n?-?3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4-). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60?-?400 (VLDL1), and Sf 20?-?60 (VLDL2) according to APOE genotype.Postprandial TRL fractions were obtained in 11 E4+ (?3/?4) and 12 E4- (?3/?3) male from the SATgen? study following high saturated fat diet?+?3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography.At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P?=?0.046) as well as a trend towards higher relative% of EPA (P?=?0.063) in the Sf >400 fraction of E4+. Total n?-?3 PUFA in the Sf 60?-?400 and Sf 20?-?60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time?×?genotype interaction (P?=?0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2?=?0.816).Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n?-?3 PUFA metabolism after receiving a high-dose of DHA.Registered at clinicaltrials.gov/show/NCT01544855.

SUBMITTER: Conway V

PROVIDER: S-EPMC4177609 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?

Conway Valérie V Allard Marie-Julie MJ Minihane Anne-Marie AM Jackson Kim G KG Lovegrove Julie A JA Plourde Mélanie M

Lipids in health and disease 20140916

<h4>Background</h4>We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n - 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n - 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4-). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf ...[more]

PMID: 25227179

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Project description:ObjectiveInsulin resistance is associated with impaired receptor dependent hepatic uptake of triglyceride-rich lipoproteins (TRL), promoting hypertriglyceridemia and atherosclerosis. Next to low-density lipoprotein (LDL) receptor (LDLR) and syndecan-1, the LDLR-related protein 1 (LRP1) stimulated by insulin action contributes to the rapid clearance of TRL in the postprandial state. Here, we investigated the hypothesis that the adaptor protein phosphotyrosine interacting domain-containing protein 1 (PID1) regulates LRP1 function, thereby controlling hepatic endocytosis of postprandial lipoproteins.MethodsLocalization and interaction of PID1 and LRP1 in cultured hepatocytes was studied by confocal microscopy of fluorescent tagged proteins, by indirect immunohistochemistry of endogenous proteins, by GST-based pull down and by immunoprecipitation experiments. The in vivo relevance of PID1 was assessed using whole body as well as liver-specific Pid1-deficient mice on a wild type or Ldlr-deficient (Ldlr-/-) background. Intravital microscopy was used to study LRP1 translocation in the liver. Lipoprotein metabolism was investigated by lipoprotein profiling, gene and protein expression as well as organ-specific uptake of radiolabelled TRL.ResultsPID1 co-localized in perinuclear endosomes and was found associated with LRP1 under fasting conditions. We identified the distal NPxY motif of the intracellular C-terminal domain (ICD) of LRP1 as the site critical for the interaction with PID1. Insulin-mediated NPxY-phosphorylation caused the dissociation of PID1 from the ICD, causing LRP1 translocation to the plasma membrane. PID1 deletion resulted in higher LRP1 abundance at the cell surface, higher LDLR protein levels and, paradoxically, reduced total LRP1. The latter can be explained by higher receptor shedding, which we observed in cultured Pid1-deficient hepatocytes. Consistently, PID1 deficiency alone led to increased LDLR-dependent endocytosis of postprandial lipoproteins and lower plasma triglycerides. In contrast, hepatic PID1 deletion on an Ldlr-/- background reduced lipoprotein uptake into liver and caused plasma TRL accumulation.ConclusionsBy acting as an insulin-dependent retention adaptor, PID1 serves as a regulator of LRP1 function controlling the disposal of postprandial lipoproteins. PID1 inhibition provides a novel approach to lower plasma levels of pro-atherogenic TRL remnants by stimulating endocytic function of both LRP1 and LDLR in the liver.

Project description:BACKGROUND AND OBJECTIVES:Triglyceride-rich lipoproteins may contribute to the high cardiovascular risk of patients with CKD. This study evaluated associations of apo-B and markers of triglyceride-rich lipoproteins with cardiovascular events in people with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Analyses were conducted in 9270 participants with CKD in the Study of Heart and Renal Protection (SHARP): 6245 not on dialysis (mean eGFR 26.5 ml/min per 1.73 m2), and 3025 on dialysis when recruited. Cox regression methods were used to evaluate associations of lipids with incident atherosclerotic and nonatherosclerotic vascular events, adjusting for demographics and clinical characteristics. Hazard ratios (HRs) were calculated per 1 SD higher level for apo-B, HDL cholesterol, LDL cholesterol, triglyceride-rich lipoprotein cholesterol (i.e., total cholesterol minus LDL cholesterol minus HDL cholesterol), non-HDL cholesterol, log triglyceride, and log ratio of triglyceride to HDL cholesterol. RESULTS:During a median follow-up of 4.9 years (interquartile range, 4.0-5.5 years), 1406 participants experienced at least one atherosclerotic vascular event. In multivariable adjusted models, positive associations with atherosclerotic vascular events were observed for apo-B (HR per 1 SD, 1.19; 95% confidence interval, 1.12 to 1.27), triglycerides (1.06; 1.00 to 1.13), the ratio of triglyceride to HDL cholesterol (1.10; 1.03 to 1.18), and triglyceride-rich lipoprotein cholesterol (1.14; 1.05 to 1.25). By contrast, inverse associations with nonatherosclerotic vascular events were observed for each of these lipid markers: apo-B (HR per 1 SD, 0.92; 0.85 to 0.98), triglycerides (0.86; 0.81 to 0.92), the ratio of triglyceride to HDL cholesterol (0.88; 0.82 to 0.94), and triglyceride-rich lipoprotein cholesterol (0.85; 0.77 to 0.94). CONCLUSIONS:Higher apo-B, triglycerides, ratio of triglyceride to HDL cholesterol, and triglyceride-rich lipoprotein cholesterol concentrations were associated with increased risk of atherosclerotic vascular events in CKD. Reducing triglyceride-rich lipoproteins using novel therapeutic agents could potentially lower the risk of atherosclerotic cardiovascular disease risk in the CKD population.

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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?

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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?

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