Postprandial lipemia as a cardiometabolic risk factor.

Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.909394

Vol. 30, No. 8, 2014, 1489–1503

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Review article Postprandial lipemia as a cardiometabolic risk factor

Angela Pirillo Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy IRCCS Multimedica, Milan, Italy

Giuseppe Danilo Norata Center for the Study of Atherosclerosis, Ospedale Bassini, Cinisello Balsamo, Italy Department of Pharmacological and Biomolecular Sciences, Universita` degli Studi di Milano, Milan, Italy The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine & Dentistry, Queen Mary University, London, UK

Alberico Luigi Catapano IRCCS Multimedica, Milan, Italy Department of Pharmacological and Biomolecular Sciences, Universita` degli Studi di Milano, Milan, Italy Address for correspondence: Angela Pirillo, E. Bassini Hospital, via M. Gorki 50, Cinisello Balsamo, 20092, Italy. [email protected] Keywords: Chylomicron – Postprandial lipemia – Remnants – VLDL Accepted: 24 March 2014; published online: 2 May 2014 Citation: Curr Med Res Opin 2014; 30:1489–503

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Abstract High levels of fasting circulating triglycerides (TG) represent an independent risk factor for cardiovascular disease. In western countries, however, people spend most time in postprandial conditions, with continuous fluctuation of lipemia due to increased levels of TG-rich lipoproteins (TRLs), including chylomicrons (CM), very low density lipoproteins (VLDL), and their remnants. Several factors contribute to postprandial lipid metabolism, including dietary, physiological, pathological and genetic factors. The presence of coronary heart disease, type 2 diabetes, insulin resistance and obesity is associated with higher postprandial TG levels compared with healthy conditions; this association is present also in subjects with normal fasting TG levels. Increasing evidence indicates that impaired metabolism of postprandial lipoproteins contributes to the pathogenesis of coronary artery disease, suggesting that lifestyle modifications as well as pharmacological approaches aimed at reducing postprandial TG levels might help to decrease the cardiovascular risk.

Introduction High levels of triglycerides (TG), a marker of triglyceride-rich lipoproteins (TRLs) and their remnants, play a role in cardiovascular disease (CVD)1–3. Indeed, the EAS (European Atherosclerosis Society) Consensus Panel position paper4 concluded that evidence from mechanistic and genetic studies as well as epidemiological data support a causal association of elevated TRLs and their remnants (with or without low high-density lipoprotein cholesterol [HDL-C]) with increased CVD risk. A Mendelian randomization study suggesting that lifelong exposure to remnant TRLs is causal for coronary heart disease (CHD) risk, independent of low plasma concentrations of HDL-C5 was also recently reported5. Furthermore, a genetic study indicated a causal role for TG, independent of confounding effects due to low-density lipoprotein cholesterol (LDL-C) or HDL-C, in the development of coronary artery disease (CAD)6. However, it is recognized that we still lack definitive evidence that targeting elevated TG impacts CVD outcomes. As several of the studies conducted to date have been performed in patients without clinically relevant hypertriglyceridemia, a true test of this hypothesis (i.e. elevated remnants) is still missing. TG levels are commonly measured in the fasting state; TG levels, however, increase significantly postprandially, and an important role in the pathogenesis of atherosclerosis-related diseases has been postulated for postprandial lipids. Post-alimentary lipemia was first described as an atherogenic phenomenon by Zilversmit in 19797. Later, it received more attention after the discovery that TRLs are atherogenic8 and that postprandial abnormalities in TG metabolism (increased plasma TG concentrations and prolonged postprandial response after a fatty meal) is a hallmark of patients with established CHD9. The identification of TRLs in human atheroma has provided further evidence for their direct role in atherogenesis10. TRLs penetrate the arterial wall and Postprandial lipemia as a cardiometabolic risk factor Pirillo et al.

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reach the subendothelial space causing endothelial lipid deposits, attraction of monocytes, production of inflammatory markers, and oxidative stress. The role of TG in atherosclerosis-mediated inflammation not only depends on their direct vascular cell effects, but is also related to profound changes in the functionality of HDL such as the protective effects against vascular inflammation11 and immune response12 most probably related to the enrichment with TG. In this review we will discuss the main factors that can influence postprandial lipemia, how postprandial lipemia is linked to cardiovascular disease and the available and future drugs for the control of postprandial dyslipidemia, especially in subjects at high cardiovascular risk.

Postprandial lipemia Plasma TGs are mainly transported by TRLs, which include liver-derived apolipoprotein B100 (apoB100)containing very low density lipoproteins (VLDLs), intestine-derived apolipoprotein B48 (apoB48)-containing chylomicrons (CMs), which transport diet-derived TG and cholesterol from intestine to peripheral cells, and their remnants13. All these lipoproteins are significantly increased in the postprandial state, and their levels may predict the cardiovascular risk independently of other lipid levels13. ApoB is synthesized in coordination with the activity of the microsomal triglyceride transfer protein (MTP) that, in the presence of lipids, quickly lipidates nascent apoB, resulting in a nascent apoB-containing particle14; next, the addition of neutral lipids increases the size of these particles that are then secreted into circulation (VLDLs) or in the lymphatic system (CMs). Insulin tightly regulates VLDL production: under fasting conditions, hepatic VLDL production is induced, while the increase of postprandial insulin reduces VLDL production14. The C-terminus of apoB100 produced in the liver contains the domain recognized by low-density lipoprotein receptor (LDLR) and thus mediates the high-affinity hepatic clearance of normal VLDL from plasma. The truncated form of intestinal apoB48 of chylomicrons, which lacks the C-terminus of apoB100, does not bind the LDLR14. TRL remnants are formed when apoB48-containing CMs or apoB100-containing VLDLs are converted into smaller and denser particles (remnants) following the hydrolysis of TGs by the action of lipoprotein lipase (LPL) bound to the capillary endothelium of adipose tissue and muscle. Remnant lipoproteins contain less TGs, are enriched (as percentage content) in cholesteryl esters (CE) and apolipoproteins C-I, C-II and C-III are replaced by apolipoprotein E (apoE); in addition, remnants exhibit pro-atherogenic features13. In fact, although VLDL and CM are too large for passage into the arterial intima, 1490

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their remnants are relatively smaller and may penetrate the arterial wall through non-receptor-mediated transcytosis regulated by the concentration gradient between vessel lumen and the intima and thus may be retained in the subendothelial space15,16. Unlike LDL, remnants may not require modification to become pro-atherogenic and may contribute to atherosclerosis through several mechanisms: induction of endothelial dysfunction, macrophage foam cell formation and smooth muscle cell proliferation; activation of inflammatory pathways; and effects on other lipoprotein classes, including increase of small dense LDL and decrease of HDL-C15,16. Although both CMs and CM remnant particles are significantly increased during the fed state, VLDL is predominant17,18: in fact, while about 80% of the rise in plasma TG following a fatty meal comes from large apoB48 CMs, about 80% of the increase in particle numbers is due to apoB100-containing lipoprotein (VLDL)17,18. The increase of VLDL particle number is due to both increased hepatic VLDL production and reduced VLDL catabolism; the latter being mainly due to the competition between chylomicrons and VLDLs for binding to LPL and its cofactor apoC-II. Nevertheless the major determinant of the extent of postprandial lipemia and the accumulation of CMs and CM remnants is the capacity of the clearance pathway19: subjects with low fasting TG levels have enough LPL and apoC-II available to catabolize the chylomicrons produced after a fatty meal, resulting in a controlled increase of TG levels19. In contrast, subjects with high fasting TG levels have a lower availability of LPL and/ or apoC-II that results in a higher increase in postprandial TG levels20, suggesting that fasting TG levels affect the rate of TRL clearance. In addition, in hypertriglyceridemic (HTG) subjects, the levels of apoC-III, an inhibitor of LPL activity, are increased, thus resulting in further reduction of VLDL TG clearance21. Chylomicrons also influence HDL levels, due to the TG enrichment of this lipoprotein, increase plasma clearance of apoA-I, and favor the formation of smaller pro-atherogenic LDL and dysfunctional HDL20.

Postprandial dyslipidemia Postprandial TG and lipoprotein level increase is a physiological and transitory event; however, a postprandial TRL accumulation is a key feature of the atherogenic lipid phenotype present in several pathological conditions, including insulin resistance22 and type 2 diabetes mellitus23 as well as in subjects with primary dyslipidemias such as familial hypercholesterolemia (FH)24 or combined hyperlipidemia25. In healthy people, plasma TG levels peak 3–4 h after the ingestion of a fat meal and tend to return to baseline within 6–8 h; under pathological conditions postprandial lipemia peak is 2–3-fold higher and www.cmrojournal.com ! 2014 Informa UK Ltd


prolonged; plasma TG levels remain elevated up to 10–12 h20. In addition to the increased levels, remnants isolated from dyslipidemic subjects exhibit anomalies in TG, cholesterol, apoE and apoC-III content26. The greater the magnitude and duration of the postprandial TG increase, the greater the exposure of the arterial wall to postprandial lipids and the greater the likelihood that TG will replace cholesterol ester in LDL and HDL particles.


Factors influencing postprandial lipemia The postprandial lipemic response is influenced by several factors including background dietary pattern and meal composition, lifestyle conditions, physiological and pathological conditions. In addition, genetic factors may also affect postprandial response (Table 1).

Physiological factors Age Postprandial hypertriglyceridemia is significantly higher in older compared with younger subjects27,28. However, the increasing prevalence of pediatric overweight and obesity29 and the notion that obesity in childhood predicts cardiovascular disease, led the focus of attention to preventive early approaches. Some observations have suggested that apoB48 level may be an important clinical indicator of CVD risk in overweight children, even in the presence of normal LDL-C levels30. Gender, menopausal status The increase of postprandial TG levels seems to be higher in men than in women27,31, and premenopausal women have a lower postprandial lipid response than older, postmenopausal women27. Postmenopausal estrogen deficiency is associated with an adverse fasting and postprandial lipid profile32, which would explain the increased cardiovascular risk in postmenopausal women. In fact, postmenopausal normolipidemic women exhibit a reduced CM clearance when compared with age- and fasting TG-matched pre-menopausal women32, and estrogen administration increases the clearance of remnants33. The levels of postprandial response in postmenopausal women after an oral fat-loading test also depend on the

Table 1. Factors influencing postprandial lipemia. Physiological factors Age Gender Menopausal status

Lifestyle conditions Diet composition Physical activity Smoking

Pathological factors Obesity Metabolic syndrome Type 2 diabetes

Genetic factors Apolipoproteins Lipid metabolism enzymes


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fasting lipid levels, the postprandial TG response being higher in women with mixed dyslipidemia than in hypercholesterolemic or control women34. A transient postprandial decrease in LDL particle size was also reported for women with mixed dyslipidemia, an effect not observed in hypercholesterolemic and normolipidemic subjects34, suggesting that a moderate increase of postprandial TG level may not trigger a significant decrease of LDL particle size. Postmenopausal women with heterozygous FH exhibit abnormal postprandial TG response compared with premenopausal FH women35. Postmenopausal estrogen therapy enhances the clearance of chylomicrons and chylomicron remnants36, but this beneficial effect is not observed in post-menopausal diabetic women37. In subjects with normal fasting TG levels, the postprandial concentration of chylomicron remnants is higher in normolipidemic women with CAD compared with matched controls without CAD33. The loss of protection from postprandial lipemia associated with the postmenopausal state potentially explains the lipid contribution to the increased risk of CAD and has the potential to be therapeutically corrected by nutritional or pharmaceutical interventions.

Lifestyle conditions Diet composition Postprandial lipemia is modulated by meal composition, in particular by fats, carbohydrates, fibers and proteins. The fat content of a meal influences the postprandial lipemic response: increasing amounts of fat increase postprandial TG levels; the type of fat affects the fatty acid composition of CMs and the subsequent postprandial TG response38. Also the amount and the nature of carbohydrates can affect postprandial lipemia, as glucose reduces and sucrose and fructose increase the postprandial TG response. The addition of dietary fibers may modestly reduce the postprandial TG increase by accelerating the transit of lipids through the intestine and reducing the postprandial accumulation of intestinal-derived CM38. Finally, the consumption of proteins together with a fatty meal seems to reduce postprandial lipemia, probably due, at least in part, to increased insulin production38. In addition to diet composition, the frequency of meals may also influence postprandial lipemia. For example, a three meal/day frequency resulted in reduced postprandial TG levels and higher insulin levels compared with a six meal/day frequency in obese women39. One possible explanation is that higher postprandial insulin stimulates LPL activity thus resulting in a higher postprandial TG clearance39. A previous study for two weeks in young women40 did not observe beneficial effects of a higher meal frequency on postprandial lipids compared with a low meal frequency. Postprandial lipemia as a cardiometabolic risk factor Pirillo et al.

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Physical activity Postprandial TG levels are influenced by the rate of appearance in the circulation and by the clearance rate or uptake of TGs by muscle and adipose tissue, which in turn is affected by the activity of LPL. In resting conditions, after a meal LPL is upregulated in adipose tissue but not in muscle. Physical activity increases LPL activity in the muscle through several mechanisms41, as changes in muscle LPL activity and plasmatic LPL levels correlate to changes in postprandial TG levels. However, physical activity reduces postprandial TG levels and VLDL production even after moderate exercise not able to induce LPL activity, suggesting a LPL-independent effect41. The most powerful determinant of the metabolic effect is, however, energy expenditure, as the amount of calories expended determines the benefit in both lipemia and glycemia42. In addition, exercise influences the postprandial TG response differently, depending on the meal composition and time lapse from meals42. Smoking Smokers exhibit altered fasting lipoprotein profiles, including higher TG and LDL-C and lower HDL-C and apoA-I43; in addition, low insulin sensitivity has been observed in subjects who smoke. Smoking is also associated with an altered postprandial response: smokers exhibit a greater postprandial TG elevation than non-smokers, with defective clearance of chylomicrons and their remnants, resulting in a prolonged residence time of these atherogenic particles44. Alcohol consumption Plasma TG levels increase after the acute consumption of ethanol alone, as well as when consumed before or with a mixed meal45–50 in normolipidemic subjects; ethanol seems to stimulate the hepatic secretion of large VLDL particles that compete with CMs for clearance50. In subjects with fasting hypertriglyceridemia acute alcohol intake alone was not found to be an important determinant of plasma TG levels48.

Pathological factors Obesity Increased adiposity is associated with an increased flux of free fatty acids to the liver, resulting in the stimulation of hepatic TG synthesis and insulin resistance, which in turn may further increase de novo hepatic lipogenesis and postprandial delivery of fatty acids to the liver. In the postprandial state, insulin resistance is associated with increased intestinal production of CMs51, probably responsible for the postprandial dyslipidemia observed in the insulin resistant condition. Anomalies in fasting lipids 1492


and lipoproteins, such as increased TG levels and decreased HDL-C levels, are common in obese subjects, who also exhibit a greater postprandial response compared with non-obese subjects52. However, obesity represents an independent risk factor for coronary artery disease even in subjects with normal fasting lipids53. This may be explained, at least in part, by an altered postprandial response in normotriglyceridemic obese subjects54,55. Metabolic syndrome Metabolic syndrome (MetS) is a condition characterized by the presence of at least three of the following conditions: increased waist circumference, raised TG levels, low HDL-C, elevated blood pressure and fasting hyperglycemia56. Obesity and insulin resistance represent two main causes of MetS57,58. The concurrent presence of these risk factors significantly increases the incidence of diabetes and cardiovascular risk. In the presence of insulin resistance, the anti-lipolytic effect of insulin on adipose tissue is impaired, resulting in the increase of free fatty acid levels. Subjects with MetS exhibit an increased postprandial response59–62; moreover, a positive relationship between the increasing number of MetS components and the magnitude of postprandial TG response has been shown63. Although fasting TG level is the main determinant of postprandial lipemia, abnormal postprandial TG levels have also been observed in normotriglyceridemic subjects with MetS64. The worsening of postprandial lipemia may thus contribute to the increased cardiovascular risk in subjects with MetS. Type 2 diabetes Subjects with type 2 diabetes (T2D) have an increased risk for CAD, that can be attributed to traditional cardiovascular risk factors; in these subjects, dyslipidemia (especially high fasting TG levels, low HDL-C levels) represents a key feature, with anomalies also in postprandial lipid metabolism, characterized by increased and prolonged postprandial response of both intestine- and liver-derived lipoproteins and of their remnants65,66. Postprandial dysmetabolism is associated with endothelial dysfunction, oxidative stress, inflammation and increased carotid intima–media thickness, thus suggesting that it can contribute to the increased cardiovascular risk in type 2 diabetes23. However, diabetic subjects with good glucose control and normal fasting TGs also exhibit abnormal plasma lipid response after a fat meal67. These abnormalities include increase of both large VLDL, due to insulin resistance and reduced inhibitory effect of insulin on VLDL secretion, and CM remnants, due to different mechanisms, including reduced LPL activity, reduced particle uptake in the liver, and increased secretion of smaller CMs67,68. These findings suggest that the study of the postprandial lipid profile may be more useful than the fasting lipid profile in type www.cmrojournal.com ! 2014 Informa UK Ltd


2 diabetic subjects, particularly in those with good glucose and lipid control, which otherwise will be considered at low cardiovascular risk if evaluated only on the basis of their fasting lipid levels.


Genetic factors Plasma lipoproteins undergo a series of changes in their composition and concentration during the postprandial period; therefore lipemic response is complex and is known to be influenced by many environmental and genetic factors14. Many studies were carried out during the past few years and examined single-nucleotide polymorphisms (SNPs) at individual genes or the combination of alleles that tend to be transmitted in conjunction (haplotypes), for their relation with specific traits during postprandial lipemia69. These studies, however, are characterized by a low consistency, and often lack an independent replication, which represents a major need for postprandial studies, whose major limitation is the low number of subjects enrolled owing the complexity of the experimental setting. Furthermore, evidence that SNPs may impact gene function is largely lacking. For these reasons, although several candidate genes have been proposed, we will discuss here only those with experimental and clinical evidence. As expected most of the SNPs are present in genes coding for apolipoproteins, lipid metabolism enzymes, transporter proteins, and receptors, as well as in emerging genes such as peroxisome proliferator-activated receptors (PPARs), angiopoietin-like protein 4 (ANGPLT4) and perilipin. Additional associations were reported with inflammatory genes such as interleukin-6 (IL-6) or toll like receptors (TLRs)70. Apolipoproteins The most studied genetic region with regard to postprandial lipemia is the APOA1/C3/A4/A5 gene cluster; SNPs of each gene in this cluster have been associated with alteration in the postprandial response. ApoC-III inhibits the activity of LPL and its plasma concentration is positively associated with TGs; SNPs within APOC3 coding or promoter regions have been associated with altered fasting and postprandial TGs71. Also a SNP in APOA1, the main protein of HDL14, may impact postprandial lipemia. Homozygotes for the minor allele of APOA1-2803G/A display a lower increase in both total TGs and large TRL TGs after a saturated fat overload70,71; whether this relates to the apoA-I fraction present on the surface of nascent chylomicrons remains to be addressed. ApoA-IV regulates dietary fat absorption and chylomicron synthesis, activates lecithin cholesterol acyltransferase (LCAT), and modulates LPL activation by apoC-II. Gene variations in this locus can alter postprandial lipemia: carriers of the rare allele of Thr347Ser have a lower postprandial increase of ! 2014 Informa UK Ltd www.cmrojournal.com

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TG levels associated with TRL remnants72, while data for the Gln360His variant are so far inconsistent73,74. ApoAV favors lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles; mutations in the APOA5 gene are associated with severe hypertriglyceridemia75. Two APOA5 SNPs (1131T 4C [SNP3] and 56C 4G [S19W]) are involved in the regulation of fasting and postprandial TGs and are associated with an increased susceptibility for CAD76. Mutations in other apolipoprotein genes, such as apoB, have also been associated with altered postprandial response: the R463W mutation causes low postprandial lipemia which is, in turn, associated with intestinal fat accumulation77.

Enzymes of lipid metabolism Lipases such as LPL and hepatic lipase (HL) are critically involved in the handling of lipids during the postprandial phase. Despite more than 60 different mutations of the LPL gene having been described that can result in a reduction of enzyme synthesis and activity, data on the effect of mutations and SNPs of LPL on postprandial response are controversial. While a difference between carriers of the Hind-III (H1/H2) SNP was observed78, for the S447X variant, which is one of the most frequent polymorphisms of LPL with an incidence of 17–22% in Caucasian populations79,80, both reduced, increased or unchanged LPL activity was reported and available studies failed to clearly demonstrate any difference between genotypes on postprandial lipemia81. For HL, data indicate that the presence of the A allele in the 250G/A promoter polymorphism is associated with a higher postprandial lipemic response82. Cholesterol ester transfer protein (CETP) plays a significant role in HDL metabolism and reverse cholesterol transport, and its inhibition also affects apoB protein levels83. CETP deficiency results in a low LDL/high HDL phenotype including apoE-rich large HDL. Large HDL may provide CE and apoE to CM/VLDL during lipolysis in the postprandial state, accelerating remnant lipoprotein formation and uptake in the liver. It is also of note that the magnitude of postprandial lipemia has been associated with plasma CETP concentration and lipoprotein content and size. After oral fat load, the area under the curve (AUC) of the TG, RLP-TG and apoB48 levels is remarkably decreased in homozygous and heterozygous CETP deficient subjects compared with the controls84. A common polymorphism in the CETP gene, TaqIB, was also associated with both fasting and postprandial TG levels in heterozygote FH patients85. In subjects with abnormal TG response to fat loading, carriers of the B1 allele of the TaqIB polymorphism had higher fasting and postprandial TG compared with B2 allele carriers and a gender related effect was demonstrated81,86. Postprandial lipemia as a cardiometabolic risk factor Pirillo et al.

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Indeed two SNPs, rs2575875 and rs4149272, in ATPbinding cassette transporter A1 (ABCA1), a major regulator of cholesterol efflux which is the initial and essential step in the biogenesis and formation of nascent HDL14, were also associated with lower postprandial lipemia in homozygote carriers of the wild type allele87. The potential role of ABCA1 in postprandial lipemia remains however unknown. SNPs in the following genes: glucokinase regulatory protein (GCKR), IL-6, perilipin (PLIN), transcription factor 7-like 2 (TCF7L2), the IL-1 pathway (IL1alpha and IL1beta), and TLR4 were also reported to impact postprandial lipemia69,70 although the mechanisms for these associations are unclear.

Clinical relevance of postprandial lipemia High remnant plasma levels are associated with increased risk of coronary artery disease and are significant predictors of future coronary events88. Fasting total plasma cholesterol and LDL-C are the best plasma biomarkers for prediction of CVD risk. However, several studies have suggested that non-HDL-C, a measure of cholesterol contained in all atherogenic apoBcontaining lipoproteins (including LDL, VLDL, CM and CM remnants), may be superior to LDL-C in predicting cardiovascular events89. The management of LDL-C levels, mainly based on pharmacological approaches, is extremely effective for the prevention of cardiovascular disease90. However, many patients with atherosclerosis do not exhibit high LDL-C levels; a significant number of cardiovascular events cannot be predicted by this parameter; finally, in fasting normolipidemic subjects, increased CVD risk is associated with an exaggerated postprandial lipemic response8,16,20. These observations led to the hypothesis that postprandial lipoproteins may have a causal role in atherosclerosis (Table 2).

Postprandial-induced inflammation Dyslipidemia and inflammation are risk factors for atherosclerosis, and the interaction between lipid metabolism and inflammation may contribute to the initiation and progression of atherosclerosis91. Postprandial lipoproteins may induce circulating leukocyte activation and increase the expression of leukocyte adhesion molecules in endothelial cells, thus promoting leukocyte infiltration in the intima92–95. Postprandial dyslipidemia is associated with increased oxidative stress, that may have a causative role in postprandial endothelial dysfunction96, for example by increasing the expression of endothelial scavenger receptors88. In addition, CM remnants induce foam cell formation without need of oxidation, as they can be taken up by macrophages and result in lipid accumulation88. Postprandially neutrophil counts increase as do 1494


Table 2. Clinical relevance of postprandial lipemia. Ref. PP lipemia and inflammation "Leukocyte activation; "adhesion molecule expression "Oxidative stress Foam cell formation "Neutrophil count; "pro-inflammatory cytokines "Complement component 3 "Endothelial cells activation PP lipemia and endothelial dysfunction #Flow mediated dilation PP lipemia and IMT IMT values correlate with remnant levels in healthy subjects "IMT values in T2D subjects with postprandial hypertriglyceridemia PP lipemia and CV risk Non-fasting TG levels are associated with increased CV risk High postprandial TG are associated with higher risk of MI, IHD and death Non-fasting TG levels predicts incident CV events in healthy women Non-fasting TG levels are associated with increased risk of ischemic stroke in the general population PP metabolism in primary dyslipidemias FH subjects exhibit delayed postprandial chylomicron clearance FCH subjects exhibit " hepatic VLDL production and # TG clearance PP lipemia and NAFLD/NASH The magnitude of postprandial lipemia predicts liver steatosis NASH patients have an increased TRL response after a fat load NASH subjects shows a more atherogenic postprandial lipoprotein profile

92–95 88,96 88 97 98,99 92

92,104–107

108–111 112–114

115–117 115 116 119

126,127 128

130 131 132

PP: postprandial; IMT: intima-media thickness; T2D: type 2 diabetes; CV: cardiovascular; TG: triglycerides; MI: myocardial infarction; IHD: ischemic heart disease; FH: familial hypercholesterolemia; FCH: familial combined hypercholesterolemia; VLDL: very low density lipoprotein; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; TRL: triglyceride-rich lipoprotein

pro-inflammatory cytokines97. Another inflammatory pathway related to cardiovascular disease is the complement system; a postprandial increase of C3 after a fat meal has been observed both in healthy subjects and in patients with cardiovascular disease or familial combined hypercholesterolemia98,99. Altogether these observations indicate a causal role of postprandial dyslipidemia in the inflammatory processes involved in atherogenesis.

Postprandial lipemia and endothelial function Endothelial dysfunction is one of the earliest clinical manifestations of atherosclerosis. A body of evidence suggests that in HTG patients TRLs in the fasting state and more so in the postprandial phase may increase the endothelial dysfunction by inducing a pro-inflammatory www.cmrojournal.com ! 2014 Informa UK Ltd



activation of the endothelium as well as of circulating monocytes92,100–103. At the molecular level, postprandial TRLs from type IV hyperlipidemic patients induce to a larger extent, compared with fasting TRLs, phosphorylation of p38 MAPK, CREB and IKB-a in human endothelial cells and increase the DNA binding activity of CREB, NFAT and NF-kB92. This is associated with the upregulation of a large set of pro-inflammatory genes (including VCAM-1, PECAM-1, ELAM-1, ICAM-1, P-selectin, MCP-1, IL-6, TLR-4, CD40, ADAMTS1 and PAI-1) induced by postprandial TRLs from HTG patients but not from normotriglyceridemic subjects92. Form the clinical perspective, the transient increase of TG levels following a high-fat meal induces a transient reduction of flow-mediated dilation (FMD) in healthy subjects without risk factors104–106, by inducing a temporary increase of oxidative stress96 and inflammation103. Flowdependent vasoactivity decreased significantly for at least 4 h after ingestion of a high-fat meal compared with a lowfat meal104, confirming a negative impact of fatty acids or TRLs on endothelial function. Changes in remnant levels during the postprandial phase seem to be related to the degree of endothelial dysfunction in moderately dyslipidemic subjects107. Of note during the postprandial phase, the endothelium-dependent FMD is decreased in both HTG and control subjects after 4 h and returns to basal levels in control subjects while remaining impaired in HTG subjects up to 8 h92. The composition of TRLs that profoundly differs in HTG patients versus control subjects is crucial and needs to be taken into account when discussing the effects of postprandial TRLs on endothelial function.

Postprandial lipemia and intima–media thickness In healthy normolipidemic and in mild-to-moderate hyperlipidemic subjects, a relationship between postprandial lipemia and the common carotid intima–media thickness (IMT), a surrogate marker of early atherosclerosis, has been described108–111; this relationship is independent of other clinical risk factors and plasma LDL-C and HDLC110. Postprandial dyslipidemia is a common disorder in patients with diabetes mellitus66, and patients with T2D have latent postprandial hyperlipidemia despite the apparent absence of fasting hyperlipidemia. Carotid IMT is increased in T2D patients with postprandial hypertriglyceridemia despite normal fasting TG values112. The fasting and postprandial TG levels are closely associated with IMT values in T2D subjects: normotriglyceridemic subjects (having normal fasting and postprandial TG levels) exhibit lower IMT values compared with diabetic subjects with postprandial or fasting hypertriglyceridemia113,114; when subjects with normal fasting TG were classified on ! 2014 Informa UK Ltd www.cmrojournal.com

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the basis of their postprandial TG levels, IMT thickening was significantly higher in those with the highest postprandial TG values113. These findings suggest that studying the postprandial lipemic response could be a useful approach to predict the presence of atherosclerosis in both symptomatic and asymptomatic subjects.

Postprandial TG levels and cardiovascular events Epidemiologic data indicate that non-fasting TG levels are associated with an increased risk of cardiovascular events115–117. Thus, postprandial lipemia has been shown to be an independent cardiovascular risk factor: increasing levels of non-fasting TG were associated with increased risk of myocardial infarction (MI), ischemic heart disease (IHD) and death in both men and women, although nonfasting TG was a better predictor in women than in men115. In a prospective study of 26,509 initially healthy women with median follow-up of 11.4 years, non-fasting TG levels were strongly associated with the incidence of cardiovascular events (including MI, ischemic stroke, coronary revascularization, and cardiovascular death) independent of traditional cardiovascular risk factors116; fasting TG showed only a little independent association with cardiovascular events after adjusting for total cholesterol, HDL-C and indicators of insulin resistance116. In this same population, TG as well as other lipid parameters (HDL-C, apoA-I) were found to predict CVD when measured non-fasting, contrarily to total cholesterol, LDL-C, and non-HDL-C117. A prospective study on the general population showed that stepwise increasing of non-fasting cholesterol and non-fasting TG were similarly associated with stepwise increasing risk of MI and IHD; non-fasting TG levels were found to be the best predictor in women and non-fasting cholesterol levels in men118. However, only high non-fasting TG levels were associated with increased total mortality118. In addition, non-fasting TG levels were associated with increased risk of ischemic stroke119. Altogether these observations suggest that non-fasting TGs are the best predictors of cardiovascular events compared with fasting TGs. On the other hand, patients with previous cardiovascular events exhibit an abnormal postprandial response. For example, elderly survivors of MI had an increased postprandial triglyceridemia (both total TG and CM-TG) compared with healthy subjects120. A delayed postprandial clearance of TRLs has been described in healthy offspring of MI survivors, who are at increased risk for CAD121; in these subjects an increased postprandial triglyceridemia was observed compared with matched subjects without a family history of CAD122, suggesting that a non-fasting TG increase may contribute to a pro-atherogenic lipid profile and to increase the risk of future cardiovascular events. T2D patients with prior MI have significantly higher levels of plasma TG after an oral fat load compared with Postprandial lipemia as a cardiometabolic risk factor Pirillo et al.

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T2D subjects without MI123, suggesting that an excessive postprandial lipemia in T2D may be a marker of a high-risk population.


Postprandial lipoprotein metabolism in primary dyslipidemias FH is a common inherited disorder characterized by high levels of LDL-C and premature CAD; LDL-C accumulation is mainly due to genetic defects in one of three key proteins, LDLR, apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9)83,124,125. A delay in postprandial CM clearance has been reported in both heterozygous and homozygous FH subjects126,127; the reduced LDLR activity may be partly responsible for this effect, as LDLR contributes to the clearance of CM remnants. Familial combined hypercholesterolemia (FCH) is the most frequent inherited disorder of lipid metabolism associated with an increased risk of CAD128. Subjects with FCH have an increased production of hepatic VLDL and a reduced clearance of postprandial TRLs, resulting in a higher postprandial response, which may contribute to the increased risk of premature CAD128. FCH patients exhibit a greater postprandial response and delayed TG clearance compared with FH subjects, who in turn exhibit a higher postprandial response compared with healthy matched subjects25; among the various FCH phenotypes, FCH with HTG and mixed dyslipidemia had a higher postprandial response compared with FCH subjects with hypercholesterolemia, and hypercholesterolemic FCH had a higher postprandial lipemia than hypercholesterolemic FH25, probably due to the older age of FCH subjects and to the higher prevalence of other risk factors including hypertension, diabetes and obesity. These findings suggest that subgroups of FH and FCH patients should be identified for earlier intervention as they might be at even higher risk of cardiovascular events.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) The liver plays a central role in the homeostasis of lipids, proteins and carbohydrates; NAFLD is a chronic liver disease probably related to lifestyle factors and characterized by the increased hepatic accumulation of lipids129. The liver takes up circulating free fatty acids, LDL and remnants; thus, postprandial lipid levels contribute substantially to the hepatic TG content in NAFLD, and the magnitude of postprandial lipemia predicts liver steatosis129. NAFLD represents a cluster of liver diseases ranging from simple steatosis to NASH, advanced fibrosis, cirrhosis and end stage liver failure. NAFLD is strongly associated with obesity, hypertension, dyslipidemia and insulin resistance129, and hyperlipidemia is a common 1496


disorder in a large number of patients with NASH, suggesting NAFLD as a cardiovascular risk factor and a candidate for early therapeutic intervention. Non-obese nondiabetic subjects with biopsy-proven NASH exhibit a higher postprandial response to an oral fat load test compared with matched controls130; the higher postprandial lipid response may contribute to hepatic TG accumulation, as the magnitude of free fatty acid response was significantly correlated with the severity of hepatic steatosis130. NASH patients had a rapid increase of plasma TG mostly due to the elevated level of large TRL particles compared with matched healthy controls131; in fact, NASH subjects exhibit an impaired ability to control TG levels after fat intake, due to their insulin resistant state131. An impaired postprandial TG metabolism may in turn promote fatty liver by increasing hepatic uptake of TRLs and their remnants in the postprandial state. Compared with subjects with simple steatosis, NASH subjects showed a more atherogenic postprandial lipid profile (TG and VLDL increase, HDL-C and apoA-I decrease) despite similar fasting values132.

Pharmacological approaches affecting postprandial lipemia The large majority of drugs affecting lipid metabolism affect also postprandial lipemia; however, well designed and robust clinical studies in this specific field are limited due the difficulties of setting up a postprandial study in a large cohort of patients. We will discuss the available evidence with established as well as emerging drugs.

Omega-3 fatty acids A few studies demonstrated that fish oil supplementation reduced fasting TG levels and postprandial TG response but with an inconsistent effect on fasting apoB48 concentrations and postprandial apoB48 response. In humans, while Tinker et al.133 showed that postprandial TRL apoB reduction is likely caused by omega-3 fatty acid mediated suppression of both hepatic and intestinal apoB secretion/synthesis, Slivkoff-Clark et al.134 showed that fish oil independently improved plasma TG homeostasis but did not resolve hyper-chylomicronemia. Instead, combining fish oil with chronic exercise reduced the plasma concentration of pro-atherogenic CM remnants134; in addition it reduced the fasting and postprandial TG response in viscerally obese insulin resistant subjects134. In nonobese subjects a high-fish diet decreased TRL apoB48 concentration by reducing the secretion rate and the fractional catabolic rate of apoB48135. Omega-3 fatty acid supplementation significantly reduced mean fasting and postprandial TG136 and accelerated chylomicron TG www.cmrojournal.com ! 2014 Informa UK Ltd


clearance by increasing LPL-mediated lipolysis137. Two new formulations of omega-3 fatty acids (AMR101 and an ultrapure mixture of free fatty acid forms of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are under clinical development and may provide additional TG-lowering effects by reducing VLDL production and increasing their catabolism thus potentially affecting also postprandial lipemia.


Niacin Niacin might lower postprandial TG by restricting the availability of free fatty acids for lipoprotein synthesis138,139. Although it takes several days to lower cholesterol, immediate-release niacin suppresses postprandial TG within hours of the first dose140 indicating that this is an acute response. Extended-release niacin (ERN) had no such benefit141. Recent evidence, however, showed that given right before a fat meal, even a single dose of ERN suppresses postprandial triglyceridemia142. This suggests that postprandial TG suppression is an acute effect of ERN, probably resulting from a marked free fatty acid restriction. Although further studies are required to determine whether mealtime dosing would augment the clinical efficacy of ERN therapy, this formulation is no longer available due to the negative results of HPS2THRIVE143 and AIM-HIGH trials144. In summary, further investigations of the dynamic effects of niacin on TRL metabolism are warranted.

Fibrates Several studies have proven the efficacy of fibrates in reducing postprandial lipemia by increasing LPL activity, decreasing apoC-III production and increasing hepatic fatty acid oxidation as well as by decreasing secretion of VLDL particles, resulting in a significant reduction of TG levels (up to 50%)145. The GOLDN study showed that fibrate response in both the fasting and postprandial phase is affected by apoE polymorphisms, with E2 carriers exhibiting an increased postprandial response146.

Statins Several kinetic studies have been conducted to examine the effect of statins on postprandial lipoprotein metabolism as reviewed by Kolovou et al.147. Statins are effective in correcting postprandial endothelial dysfunction in obese and T2D patients148–150. Whether the beneficial effects of statins are related to a decreased production or to an increased catabolism of lipoproteins is debated. Indeed Chan et al. showed that in insulin-resistant, centrally obese individuals, atorvastatin significantly reduced plasma concentrations of apoB48 by accelerating the ! 2014 Informa UK Ltd www.cmrojournal.com

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catabolism of CM remnants151; while Hogue et al. found that in T2D, atorvastatin reduced TRL apoB48 levels because of a significant decrease in its production152. We tested the impact of atorvastatin on apoB100 and apoB48 levels in diabetic patients; we observed an effect of atorvastatin only on apoB100 but not on apoB48 plasma level increase during the postprandial phase (Catapano et al., unpublished data). Further studies are needed to clarify the impact of statins on apoB48 kinetics in HTG. Unpublished data from our group (Grigore et al.) also suggest that, in dyslipidemic patients, rosuvastatin treatment corrects the fasting lipid profile and the AUC of postprandial cholesterol levels in TRLs, but does not affect postprandial plasma TG levels.

Ezetimibe Ezetimibe inhibits intestinal cholesterol absorption by blocking the protein Niemann-Pick-type C1-like 1 (NCP1L1)83. Although several clinical trials have also consistently demonstrated that ezetimibe alone or combined with a statin beneficially influences postprandial lipemia153–155, the mechanisms beyond this effect are debated and so far only one study in humans has clearly indicated that ezetimibe plus simvastatin reduced plasma TRL apoB48 levels by reducing TRL apoB48 secretion in men with mixed hyperlipidemia156. In a double blind crossover trial, ezetimibe was shown to restore the postprandial dysregulation of lipids but did not affect glucose metabolism in obese subjects with dyslipidemia157. As ezetimibe could also improve liver fat content158, the possibility that this mechanism could contribute to the improved postprandial response should be investigated.

MTP inhibitors MTP is an essential protein in the synthesis of VLDL and CM; interfering with this process is therefore an attractive approach for reducing lipoprotein synthesis and decreasing plasma lipoprotein concentration83. The MTP inhibitor lomitapide has recently terminated phase III testing and was approved for FH patients159. Based on the mechanism of action, beneficial effects on postprandial lipemia are expected, although the adverse effects such as elevated liver enzymes and hepatic fat accumulation (predictable from the mechanism of action) were reported and may restrict the patient population for this drug83.

Alipogene tiparvovec (AAV1-LPLS447X) A number of studies have been carried out to assess the safety and efficacy of a novel gene therapy approach (alipogene tiparvovec) for the treatment of adult lipoprotein lipase deficient (LPLD) patients160. Alipogene tiparvovec Postprandial lipemia as a cardiometabolic risk factor Pirillo et al.

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contains the coding sequence for LPLS447X, a naturally occurring gain of function variant of LPL within a recombinant adeno-associated virus of serotype 1 (AAV1)160. In an open-label clinical trial, intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial CM metabolism in LPLD patients, without inducing large postprandial non-essential fatty acid (NEFA) spillover161. The overall result is a much reduced postprandial level of newly formed, large/buoyant chylomicrons, which are thought to be the most pathogenic and causal in eliciting acute (recurrent) pancreatitis in lipoprotein lipase deficient subjects160,161. Although effective, this strategy so far is limited to a restricted number of patients and cannot be easily translated to a larger group.

ApoB and apoC-III gene silencing Gene silencing mediated by the injection of small nucleic acids molecules is one of the most promising pharmacological approaches. Antisense oligonucleotides (ASOs) and short interfering RNA (siRNAs) both complementary to the mRNA of interest are currently under pre-clinical and clinical development for the management of dyslipidemia162. The development of apoB silencing strategies represents so far the most advanced gene silencing approach under clinical development. Mipomersen, an ASO targeting apoB leading to a dose-dependent reduction in apoB and total cholesterol, was recently approved by the FDA for FH patients83,162. This drug reduces apoB, LDL-C and VLDL levels, as well as total plasma and lipoprotein-associated apoCIII163,164; based on these observations, beneficial effects on postprandial lipemia are expected. Another protein expressed in the liver which plays a central role in the regulation of plasma triglycerides is apolipoprotein C-III. ApoCIII Rx, an apoC-III antisense inhibitor is currently being tested in a phase II study in patients with TG levels 500 mg/dL. The study will evaluate ISISAPOC-III Rx as a monotherapy and in combination with fibrates in patients with severe hypertriglyceridemia (http://clinicaltrials.gov/ct2/show/ NCT01529424). The endpoints of the study include measurements of circulating TG and apoC-III levels before and after eating.

Diacylglycerol O-acyltransferase-1 (DGAT-1) inhibitors DGAT-1 catalyzes the formation of an ester linkage between a fatty acyl-CoA and the free hydroxyl group of diacylglycerol, a key step in the synthesis of TGs. Inhibition of DGAT-1 therefore represents a novel approach to treating hypertriglyceridemia and LCQ908, 1498


a new class of DGAT-1 inhibitor, is now in phase II and phase III development for the treatment of hypertriglyceridemia165. Given the mechanism of action it is expected that postprandial response might also be positively affected by DGAT-1 inhibitors.

Conclusions Increasing evidence indicates that impaired metabolism of postprandial lipoproteins contributes to the onset of coronary artery disease. The levels of lipoprotein remnants are highly correlated with the incidence of cardiovascular disorders115,118,119 and therefore the possibility of controlling postprandial lipemia is of great clinical interest. Established and emerging therapeutic approaches can influence the degree of postprandial lipemia but how and whether this contributes to the vascular protective effects of the drugs is still understood and studies at the molecular level are warranted to fill the gap between the clinical evidence of a beneficial effect of postprandial lipid profile and potential atheroprotective mechanisms. Furthermore the magnitude of the impact of lifestyle modifications as well as pharmacological approaches aimed at reducing postprandial TG levels on cardiovascular risk largely change according to the population studied and the methodological approach used for addressing postprandial lipemia. Translating postprandial lipemia in the clinical setting is far from being complete and, until a standardized oral fat load is established the investigation of postprandial lipemia is confined to research centers. Furthermore a consensus on the parameters other that the TG postprandial curve that should be investigated to better understand the different atherogenic potential of TG rich lipoproteins103 is warranted. To this aim, the evaluation of flow mediated dilatation92, circulating biomarkers of the metabolic status166,167, peripheral blood mononuclear cells gene expression profile103 or of the effect of specific TRL fractions on endothelial cells and macrophage gene expression/function101,102 might represent an alternative approach. In summary, although fat loading tests need standardization168,169 as they are a more complex compared to the glucose tolerance test, a careful evaluation of postprandial lipemia will help to better stratify patients with dyslipidemia and hypertriglyceridemia.

Transparency Declaration of funding This study was not funded. Declaration of financial/other relationships A.P. and G.D.N. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. A.L.C. has disclosed that he

www.cmrojournal.com ! 2014 Informa UK Ltd



has received grants from and is a consultant to Merck, AstraZeneca, Amgen, and Sanofi. He has also been a consultant to Pfizer. CMRO peer reviewer 1 has disclosed that he is the recipient of sponsorship funding to attend meetings on behalf of Merck, Sharpe & Dohme; is a consultant for Merck, Sharpe & Dohme; and is a member of the speakers bureaux for Merck, Sharpe & Dohme and Genzyme. CMRO peer reviewer 2 has no relevant financial or other relationships to disclose.

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1503

Postprandial hypertriglyceridemia as a coronary risk factor.

Femoral lipectomy increases postprandial lipemia in women.

Postprandial lipemia, fenofibrate and coronary artery disease.

Exercise and dietary-mediated reductions in postprandial lipemia.

Postprandial lipemia: reliability in an epidemiologic field study.

Resistance Exercise Attenuates High-Fructose, High-Fat-Induced Postprandial Lipemia.

Low-density lipoprotein electronegativity is a novel cardiometabolic risk factor.

Postprandial lipemia and the risk of coronary heart disease and stroke: the Atherosclerosis Risk in Communities (ARIC) Study.

Postprandial hypotension as a risk marker for asymptomatic lacunar infarction.

Acute and chronic effects of sprint interval exercise on postprandial lipemia in women at-risk for the metabolic syndrome.

Complement C3 as a marker of cardiometabolic risk in psoriasis.

Sedentary behaviour as an emerging risk factor for cardiometabolic diseases in children and youth.

Sleep Debt and Postprandial Metabolic Function in Subclinical Cardiometabolic Pathophysiology.

Factors associated with postprandial lipemia and apolipoprotein A-V levels in individuals with familial combined hyperlipidemia.

Phosphorus supplement alters postprandial lipemia of healthy male subjects: a pilot cross-over trial.

Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men.

Effect of acute interval sprinting exercise on postprandial lipemia of sedentary young men.

Increased participation in weekend physical activity reduces postprandial lipemia in postmenopausal women.

Resistance exercise at variable volume does not reduce postprandial lipemia in postmenopausal women.

Energy replacement using glucose does not increase postprandial lipemia after moderate intensity exercise.

Influence of olive oil on carotenoid absorption from tomato juice and effects on postprandial lipemia.

Effects of moderate- and intermittent low-intensity exercise on postprandial lipemia.

Aldosterone: a cardiometabolic risk hormone?

Clinical considerations and mechanistic determinants of postprandial lipemia in older adults.