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 (>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 <0.01). Postprandial AUC of TG, apoCIII, ANGPTL3, VLDL, chylomicrons (apoB48) reduced by 35%, 34%, 40%, 17%, 19% (p <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.

Abstract 30: ApoE and ApoCIII Interact to Modulate the Metabolism of HDL ApoA-I in Humans

ApoE has potential roles in HDL metabolism by promoting enlargement and clearance, and apoCIII could delay apoE-mediated clearance by the liver as it does for VLDL metabolism. To determine whether apoE and apoCIII modulate the kinetics of apoA-I HDL, we compared the metabolism of apoA-I in HDL subspecies that have apoE, apoCIII, both, or neither. We recruited 10 participants (4M, 6F) with low HDL-C (range 24-54 mg/dl) and BMI between 25-35 kg/m 2 . They were given an IV bolus of d3-leucine and blood collected up to 46hr. HDL was isolated from plasma by anti-apoA-I immunoaffinity chromatography, separated by sequential anti-apoE and anti-apoCIII chromatography, and size-separated using NDPAGE into alpha-1, alpha-2, alpha-3, and prebeta-1 HDL. ApoA-I was purified from HDL subspecies on SDS-PAGE, and pool size of apoA-I was determined from the protein bands, adjusted to plasma total apoA-I. D3-leucine enrichment was measured by GC-MS. We used SAAM-II modeling software to compute apoA-I fractional catabolic rates (FCR) and fluxes for each HDL subspecies using a published multicompartmental model. The main findings from our preliminary model investigation are: - The liver secretes a range of HDL sizes for each of these HDL subspecies. About 2-6% of plasma HDL apoA-I is associated with apoE and/or apoCIII. Regardless of size, apoE- and apoCIII-containing HDL are detectable in the circulation slightly earlier after tracer administration than HDL containing neither apoE nor apoCIII. - HDL that contains apoE but not apoCIII is especially active in size conversions, such as generating prebeta-1 HDL. Prebeta-1 HDL types are not a universal precursor of larger size HDL. - HDL that contains apoE but not apoCIII has about a 4-fold increased FCR (range 1.3-8.8) across all sizes of HDL compared to other HDL subspecies, consistent with the role of apoE as a liver receptor ligand. When coexisting with apoE, apoCIII abolished the apoE-accelerated clearance, making the FCR similar to that of HDL that does not have apoE. But, when apoCIII is present on HDL that does not have apoE, there is no reduction in clearance compared to HDL containing neither apolipoprotein. In conclusion, these results suggest that apoE accelerates the metabolism of HDL apoA-I, whereas apoCIII impedes this process.

Very Low Density Lipoprotein Metabolism and Plasma Adiponectin as Predictors of High-Density Lipoprotein Apolipoprotein A-I Kinetics in Obese and Nonobese Men

Context: Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations. Objective: We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations. Study Design: The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques. Results: In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups. Conclusions: Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.