Invited critical reviewPostprandial hypertriglyceridemia as a coronary risk factor
Introduction
Despite a dramatic reduction in mortality from cardiovascular disease (CVD) in recent decades, CVD is still the major killer in the western world. In particular, individuals with obesity-associated disturbances in metabolism, such as insulin resistance and type 2 diabetes (T2D), remain at high risk of cardiovascular events [1]. The mechanisms behind this increased risk are not fully understood. Epidemiological studies have identified non-fasting (postprandial) triglyceride (TG) concentrations as a clinically significant risk factor for CVD [2], [3], [4]. TGs are carried in chylomicrons (CMs) and very low-density lipoproteins (VLDLs), which are synthesized in the intestine and liver, respectively. Lipolysis of these triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) results in the formation of smaller remnant particles that are TG depleted and enriched in cholesteryl esters [5]. For many years, CMs and CM remnants were thought to be the major culprits in postprandial hyperlipidemia [6], [7]. However, the major increase in the postprandial lipoproteins after food intake occurs in the liver-derived VLDL remnant particles [8], [9].
Section snippets
Chylomicrons and VLDL particles
TRLs in the plasma consist of CMs carrying TG from the diet, liver-derived VLDLs and their respective remnant particles. TRLs consist of a core of neutral lipids (mainly TG but also some cholesteryl esters) surrounded by a monolayer of phospholipids, free cholesterol and proteins. Each TRL particle contains one molecule of apolipoprotein B (apoB), one of the largest proteins in the mammalian cell and the ligand for the low-density lipoprotein (LDL) receptor [10], [11]. ApoB exists in two forms,
Uptake of dietary fat and formation of CMs
The human intestine is equipped to efficiently absorb dietary fat predominantly in the form of TGs. After eating a meal, TG is hydrolyzed by lipase to yield fatty acids (FAs) and monoacylglycerol, which are then absorbed into the enterocytes. Within the enterocyte, FAs can be: (1) used for synthesis of cholesteryl esters or phospholipids; (2) oxidized; (3) re-esterified to form TG for incorporation into CMs; or (4) stored as TGs in cytoplasmic lipid droplets. The multistep assembly of CMs
Regulation of the secretion of apoB-containing lipoproteins
The secretion of TRLs has been extensively studied, but mainly in liver cells. It is today well known that the secretion of VLDL is reduced by insulin, and hepatic insulin resistance is linked to an oversecretion of VLDL [32], [33], [34], [35], [36], [37], [38]. Increased liver fat in humans is linked to overproduction of large TG-rich VLDL (VLDL1 particles) [34], which is not surprising given that VLDL formation is dependent on lipid availability. The most common form of liver steatosis is
Intravascular lipolysis of TRLs
After secretion of TRLs from the intestine and liver, TGs are removed from the lipoproteins by LPL allowing the delivery of free FAs to muscle and adipose tissue. As the TGs are removed and density increases [62], CMs become CM remnants, and large TG-rich VLDL1 particles become smaller VLDL2 and subsequently IDL. IDL can be further hydrolyzed by hepatic lipase (HL) to LDL, which is catabolized mainly by hepatic uptake of LDL through LDL receptors [63]. Since the TRLs contain a substantial
Definition of hypertriglyceridemia
The tradition has been to measure TG after an overnight fast and guidelines have defined a desirable ‘normal’ level of fasting serum TG to be < 1.7 mmol/l (< 150 mg/dL) [1], [92]. The classification of elevated serum TG is generally based on fasting values, which vary in different guidelines [93]. Fasting TG cut-off values for diagnosis of hypertriglyceridemia have varied from 1.7 to 2.3 mmol/l (from 150 mg/dL to 199 mg/dL). Recently, a re-definition of hypertriglyceridemic states has been proposed to
Genetic variants causing postprandial lipemia
As the metabolic machinery of postprandial TRL species comprises several steps at the intestine level, in the circulation and in the liver the genetic control of these processes has been associated with several variants in multiple genes modifying different steps. The current approach has been to look at identified polymorphisms of specific candidate genes regulating the metabolic steps. The small number of subjects and variability of study designs have further hampered the conclusions
Epidemiological and clinical evidence for high TG levels in CVD
The significance of fasting and postprandial TGs in CVD has been debated since Zilversmit's proposal in 1979 that CMs and their remnants are atherogenic [98]. Today it is well accepted that, because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller LDL particles [99]. However, since remnant particles not only contain TGs but also approximately 40 times higher levels of cholesteryl esters per particle compared with LDL [99], elevated levels of remnants
Epidemiological evidence for remnant particles in CVD
The estimate of circulating atherogenic particles is improved by measuring non-fasting remnant lipoprotein cholesterol in addition to TG. The strongest evidence and validation of non-fasting lipid measurements are from the Copenhagen City Heart study [2], [114]. After 31 years of follow-up, non-fasting cholesterol remained the best predictor of myocardial infarction in men [112]. Remnant-like particles (RLP) are isolated from serum samples by the immune adsorption method with the monoclonal
Postprandial lipids in populations with CVD: case–control studies
Case–control studies comparing the magnitude and time-frame of postprandial lipemia in CHD patients are few and limited in number of subjects. These studies used highly variable fat loads, sampling times and methodology for analysis, and are therefore not directly comparable.
Data accumulated from rather small studies on CVD clearly demonstrate abnormal postprandial TG and remnant particle metabolism in both subjects with vascular disease and their relatives (reviewed in [94]). The main findings
Assessment of postprandial TRL metabolism
Emerging evidence in support of the power of non-fasting TG levels to predict CVD risk and postprandial dysmetabolism identifies an urgent need to define accurate and standardized methodology to assess different components of TRLs in the postprandial state. The heterogeneity of TRLs with respect to size and apolipoprotein composition represents a challenge. In addition, there is a need to set clinical reference standards for each component, and the methodology to measure these markers should be
Management of hypertriglyceridemia
Current guidelines acknowledge elevated fasting and postprandial TG levels as important risk factors for CVD [1], [148]. It is also well established that the risk of pancreatitis is clinically significant if plasma TG values exceed 10 mmol/L, and that subjects with such high TG levels need immediate pharmacotherapy in addition to intense dietary changes and restriction of calories and fat content in the diet.
Data from randomized clinical trials on the clinical benefits of lowering TG are much
Concluding summary
In the postprandial state, TRLs comprise CMs synthesized in the intestine, VLDL particles produced in the liver and their cholesterol-rich remnants. Postprandial hypertriglyceridemia can be initiated by both overproduction and/or defective catabolism of TRLs and is caused by both genetic variations and non-genetic factors such as obesity or T2D. Remnants can accumulate in the arterial wall and will deliver more cholesterol than LDL particles. Recent data strongly indicate that both non-fasting
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