The status of fasting triglycerides as a risk factor for coronary artery disease (CAD) has been considered weak because in multivariate analyses, triglycerides tend to be eliminated by high density lipoprotein (HDL) cholesterol. To further evaluate the role of triglycerides in CAD, we employed postprandial lipemia as a more informative means of characterizing triglyceride metabolism. In 61 male subjects with severe CAD and 40 control subjects without CAD as verified by angiography, we measured cholesterol; triglycerides; HDL cholesterol; HDL2 cholesterol; and apolipoproteins A-I, A-II, and B in fasting plasma and triglycerides before and 2, 4, 6, and 8 hours after a standardized test meal. Both the maximal triglyceride increase and the magnitude of postprandial lipemia (area under the triglyceride curve over 8 hours after the meal) were higher in cases than in control subjects. Single postprandial triglyceride levels 6 and 8 hours after the meal were highly discriminatory (p < 0.001), and by logistic-regression analysis displayed an accuracy of 68% in predicting the presence or absence of CAD. In this respect, accuracy was higher than that of HDL2 cholesterol (64%) and equal to that of apolipoprotein B (68%), the most discriminatory fasting parameter. Multivariate logistic-regression analysis was performed to reduce the number of risk factors to those that were statistically independent. This statistical procedure selected postprandial but not fasting triglycerides into the most accurate multivariate model, which also contained the accepted risk factors HDL2 cholesterol, apolipoprotein B, and age. This model classified 82% of subjects correctly. We conclude that triglycerides are independent predictors of CAD in multivariate analyses including HDL cholesterol, provided that a challenge test of triglyceride metabolism such as postprandial lipemia is used. The study suggests that the metabolism of triglycerides is a critical determinant of cholesterol metabolic routing. The findings support the concept that the negative association between HDL cholesterol levels and CAD actually originates in part from a positive relation between CAD and plasma triglycerides, as ascertained in the postprandial state.

Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state.

The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.

New insights into the regulation of HDL metabolism and reverse cholesterol transport.

Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.

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Cholesterol, inflammation and innate immunity

Background Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. Methods A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). Results After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of L...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa070635

Effect of Torcetrapib on the Progression of Coronary Atherosclerosis

Plasma cholesteryl ester transfer protein

Background and Methods. The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. Results. We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of Restriction-Fragment Length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [±SD], 7.01±0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24±1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-d...

https://www.nejm.org/doi/pdf/10.1056/NEJM199011013231803

Koki Takata

Papers

Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.