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.Abnormally elevated blood triacylglycerol (TAG) level in the postprandial period is a feature of metabolic syndrome (MetS) and is predictive of an increased risk of cardiovascular disease (1–3). Hypertriglyceridemia is due to excess triglyceride-rich lipoproteins (TRLs): VLDLs synthesized by the liver, containing the higher–molecular weight form of apolipoprotein (apo)B, apoB100, and chylomicrons (CMs), which are synthesized in the intestine in response to an intake of dietary fat and contain the lower–molecular weight form of apoB, apoB48. Both VLDL and CMs share a common lipolytic pathway and are hydrolyzed by lipoprotein lipase, an enzyme predominantly found on the endothelial surfaces of the capillaries of adipose tissue and heart and skeletal muscle (4).Postprandial hypertriglyceridemia in MetS may be due to the overproduction of intestinal or hepatic TRLs, impaired clearance, or a combination of both. Insulin resistance is associated with a postprandial increase in apoB48 particles (5), and some studies suggested that this is due to impaired catabolism of intestinally derived TRL and remnant lipoprotein TAG (6,7). However, the small intestine is capable of utilizing endogenous substrates for TAG synthesis. Duez et al. (8) have used a constant feeding protocol combined with an infusion of labeled leucine to measure apoB48 kinetics, a surrogate measure of intestinal TRL kinetics, in men with a range of insulin sensitivity. The study showed that insulin resistance was associated with increased intestinal apoB48 production rate. In addition, diet-induced insulin resistance in the Syrian golden hamster has been shown to be associated with a marked increase in intestinal lipoprotein production rate in both the fasting and the fed states (9), which could be reduced by treatment with rosiglitazone (10). Since insulin resistance is associated with elevated nonesterified fatty acid (NEFA) flux from adipose tissue, the mechanism that leads to apoB48 overproduction may be increased delivery of NEFAs to the enterocyte, since an acute elevation of NEFAs in hamsters has been shown to increase basal intestinal apoB48 production (11).A number of studies have shown that VLDL apoB100 and VLDL TAG production rate is increased by insulin resistance (12,13) in the fasted state, but no studies have measured VLDL TAG production rate quantitatively, in the fed state, in MetS. We have recently demonstrated that intravenously administered ²H₅-glycerol is incorporated into CM TAG and can be used to measure both CM and VLDL TAG kinetics in a frequent feeding study (14). In the current study, we have used this methodology to investigate whether the greater increase in postprandial TAG in MetS compared with lean healthy subjects is due to an increase in CM and/or VLDL TAG production rate or a decrease in clearance rate. We hypothesized that an increased synthesis of both CM and VLDL TAG in MetS would be the major cause of the increased postprandial TAG.