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Abstract A patient is described who exhibited, despite excessively high postprandial triglyceride levels, high levels of HDL cholesterol. Measurement of CETP activity and mass in the patient’s plasma showed values of less than 5% and 2%, respectively, of a normolipidemic plasma pool. The CETP cDNA of the patient exhibited a mutation (T → G), turning codon 57 (TAT) of exon 2 into a stop codon (TAG) and abolishing a, Xcm I restriction site. Digestion of directly amplified CETP cDNA from the patient with Xcm I indicated the exclusive presence of CETP cDNA containing the mutation. Analysis of the corresponding region of the CETP gene indicated the patient to be heterozygous for the nonsense mutation at codon 57, a finding that can only be explained by the presence of a null allele in addition to the allele with the nonsense mutation. The combination of TG intolerance of uncertain cause, together with CETP deficiency due to a novel mutation, produced the paradoxical constellation—high levels of HDL cholesterol (172 mg/dL) associated with a high postprandial lipemia of 1460 mg triglycerides/dL.8 hours—and provided further insight into the role of CETP as mediator between pools of triglycerides and cholesteryl esters in plasma.

Abstract Hepatic lipase has a demonstrated dual role in plasma lipid transport in that it participates in the removal of remnants of triglyceride-rich lipoproteins from the circulation and in the metabolism of plasma HDL. The study presented here investigated the substrate properties for hepatic lipase of HDL differing in density and apolipoprotein (apo) composition. Rates of fatty acid liberation were twofold higher in HDL 2 compared with the respective HDL 3 subspecies. Within each density class, enzyme-catalyzed fatty acid release was nearly twofold higher from HDL containing apoA-II compared with HDL devoid of apoA-II. When native HDL 3 devoid of apoA-II was reconstituted with dimeric apoA-II in vitro, rates of fatty acid liberation in reconstituted particles were similar to those in native HDL 3 containing apoA-II. HDL containing apoA-II competed more effectively with small VLDL for binding of hepatic lipase than HDL devoid of apoA-II. HDL 3 , particularly apoA-II–containing HDL 3 , reduced lipolysis of triglyceride and total fatty acid liberation in small VLDL. We conclude that the substrate properties of HDLs for hepatic lipase are influenced by both their size and apoA-II content. Moreover, size as well as apoA-II content may indirectly affect remnant clearance.

Objective— Lipolysis of triglyceride-rich lipoproteins (TGRLPs) generates phospholipid-rich surface remnants and induces cytotoxic effects in adjacent vascular cells. We hypothesized that by integrating surface remnants into HDL, phospholipid transfer protein (PLTP) alleviates cytotoxicity. Methods and Results— To test this hypothesis and gain insight into cytotoxicity during the postprandial phase in vivo, we injected normo-TG and hyper-TG human volunteers after a standardized fat meal (postprandial sample) with heparin, thereby stimulating lipolysis (postprandial heparinized sample). Incubation of (primary) human macrophages and primary human endothelial cells with postprandial heparinized hyper-TG plasma induced pronounced cytotoxic effects that were dose dependent on the TG content of the sample. No such effects were seen with normo-TG and postprandial hyper-TG plasma. In vitro lipolysis of VLDL and chylomicrons indicated that both lipoprotein fractions can cause cytotoxicity. Interestingly, in experiments with THP-1–derived macrophages stably transfected with PLTP, PLTP substantially augmented both net phospholipid uptake and apoptotic cell death due to postprandial heparinized hyper-TG plasma. We observed that activation of caspase-3/7, poly-ADP-ribose polymerase, and enhanced bioactivity of acid sphingomyelinase may all contribute to this augmented apoptosis. Conclusions— Our data show that lipolysis of TGRLPs and their remodelling by PLTP interact to disturb cellular phospholipid flux and intracellular signaling processes, ultimately leading to apoptosis in human macrophages and endothelial cells.

Objective— Obesity is associated with increased morbidity and mortality from atherosclerotic disease. Lipid abnormalities contribute to the increased relative risk in obese subjects. Cholesteryl ester transfer protein (CETP) mass is increased in these patients and might mediate the atherogenic lipoprotein pattern observed in obesity. Methods and Results— Twenty-one morbidly obese, middle-aged, female subjects participated in this prospective study. Subjects were examined before and 1 year after surgical treatment. Fat mass was determined by body impedance analysis; CETP mass, by ELISA; CETP activity, by exogenous substrate assay; and LDL particle diameter, by gradient gel electrophoresis. Mean weight loss after 1 year was 28.7 kg; mean fat mass loss was 22.6 kg. Mean CETP mass decreased from 1.81 to 1.32 μg/mL ( P =0.008); mean CETP activity decreased from 244 to 184 nmol · mL −1 · h −1 ( P =0.004); and in parallel, the mean diameter of LDL particles increased (256.8 to 258.4 Å, P =0.04). Conclusions— We conclude that weight loss is associated with a pronounced decrease in CETP mass and activity and a consistent increase in LDL particle diameter. After 1 year of this prospective study in morbidly obese subjects undergoing weight loss by surgical treatment, it has been determined that some features of the atherogenic lipoprotein profile can be reversed.

To evaluate the independent effect of cholesteryl ester transfer protein (CETP) on HDL concentrations in humans, we measured lipids, lipoproteins, postprandial lipemia after an oral fat load, CETP mass, and the activities of CETP, lipoprotein lipase (LPL), and hepatic lipase in 16 healthy, normotriglyceridemic men and in 23 men with moderate, primary hypertriglyceridemia on an American Heart Association Step I diet. Fasting triglycerides and postprandial lipemia were increased and HDL cholesterol (HDL-C) was decreased in hypertriglyceridemic men compared with control subjects ( P P P r =−.504, P =.014). Structural equation modeling of the association structures between HDL and fasting and postprandial triglycerides, endothelial lipases, and CETP in both groups indicated that the overall regression models for the two groups differed ( P P