Remnant Lipoproteins and Atherosclerotic Disease
The function of serum lipoproteins is to deliver hydrophobic lipids (triglycerides) and sterols (cholesterol, cholesterol esters) to systemic tissues within an aqueous phase (plasma). Phospholipids, apoproteins, and cholesterol comprise the surface coat of lipoproteins, while triglycerides and cholesterol esters are concentrated in the core of these particles. The triglycerides are hydrolyzed and consumed as oxidizable substrate by such tissues as skeletal muscle and myocardium while the cholesterol can be used to modulate cell membrane fluidity and serve as a substrate for steroid hormone biosynthesis, among other functions. Lipoproteins are highly specialized and are separated according to density. Low-density lipoprotein cholesterol (LDL-C) is highly atherogenic and is a defined target of therapy for reducing risk of cardiovascular (CV) events by specialty societies around the world.1-3 Treatment targets and thresholds for non-high-density lipoprotein cholesterol (non-HDL-C defined as total cholesterol minus HDL-C) were also defined by these societies. The latter is particularly noteworthy since non-HDL-C has been shown to be a stronger predictor of risk in the secondary prevention setting4 than LDL-C and encompasses the cholesterol in all atherogenic lipoprotein fractions, including remnant particles, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lipoprotein(a) [Lp(a)].
Chylomicrons and VLDLs are receiving much more intense scrutiny for their roles in atherogenesis. Chylomicrons are formed in jejunal enterocytes. A nascent chylomicron particle is comprised of apoB48 (a truncated version of apoB100, the principal apoprotein constituent of the hepatically derived lipoproteins VLDL, IDL, and LDL), phospholipid (PL), cholesterol ester (CE), and triglyceride (TG). Chylomicrons are responsible for delivering lipid derived from dietary and biliary sources to the liver. They are secreted into the perimesenteric lymphatics and enter the central circulation through the thoracic duct. Along the way, HDL particles transfer a variety of apoproteins (E, CI, CII, CIII) to these nascent chylomicrons. Apo CII is an activator of the enzyme lipoprotein lipase (LL). LL hydrolyzes triglycerides within the core of chylomicrons, thereby releasing free fatty acids, a readily oxidizable source of energy. As the triglycerides are progressively stripped away, chylomicron remnants (CR) are formed which constitute incompletely digested chylomicrons. Under normal physiological conditions, these CR are taken up into the space of Disse (the subendothelial space in hepatic sinusoids). If the remnant particle does not already contain apoE, it can take up apoE secreted by hepatocytes. The CRs are cleared by hepatocytes after binding via apoE to either heparin sulfate glycosaminoglycans or the LDL receptor-related protein. The hepatocytes then break down the CRs into their constituent lipids. Some of the lipid so released can then be repackaged into nascent VLDL particles and then secreted into the central circulation. Once in the circulation, HDL particles can transfer apoproteins to the VLDL particle surface which promotes lipolysis (apo CII) and clearance (apoE). Under normal circumstances the VLDL is progressively lipolyzed to form progressively smaller VLDLs (VLDL1, then VLDL2, then VLDL3), IDL, and then LDL.
Under normal physiological conditions lipoprotein production, metabolism, and clearance are efficient processes. However, given the high prevalence of atherosclerotic disease throughout the world, derangements in lipids and lipoproteins are epidemic. Among the most important metabolic derangements giving rise to impaired metabolism and clearance of chylomicrons and VLDLs are obesity, insulin resistance/metabolic syndrome, and diabetes mellitus (DM).5,6 Insulin resistance (IR) induces a broad variety of disturbances in lipid metabolism.7 As adipocytes become insulin resistant, insulin can no longer appropriately inhibit hormone sensitive lipase (HSL), which leads to constitutive release of free fatty acid (FFA) from intracellular triglycerides stores. The FFAs are taken up into hepatocytes via the portal circulation and can then undergo any of four fates: (1) be taken up into the mitochondrial matrix and undergo beta-oxidation; (2) be reassimilated into triglyceride and secreted in VLDL particles; (3) be shunted toward gluconeogenesis and worsen the hyperglycemia of IR; and (4) undergo deposition as triglyceride leading to hepatic steatosis. In the setting of IR, insulin has reduced capacity to inhibit the hepatic secretion of VLDLs in the fed state. In addition, in patients with IR, apo CII is less available and apo CIII (an inhibitor of LL) production is increased. As the amount of secreted VLDL particles increases, LL activity is reduced and VLDL remnants and IDL accumulate with less formation of LDL. In an effort to offload triglyceride from remnant lipoproteins (VLDL 2+3 and IDL; RLPs), cholesterol ester transfer protein is activated which catalyzes a 1:1 stoichiometric exchange of triglyceride out of remnants lipoproteins in exchange for cholesterol ester from HDL and LDL particles.8 As the HDL and LDL particles become progressively more enriched with triglyceride, they become better substrates for lipolysis by hepatic lipase. This leads to HDL catabolism and a reduction in circulating levels of HDL-C and an increase in small, dense LDL particles, the so-called atherogenic dyslipidemia: low HDL-C, large number of LDL particles, and hypertriglyceridemia characterized by significant elevations in circulating RLPs.
Serum lipids are measured typically after an 8-12 hour fasting. In Western societies, during routine daily living, the majority of people are persistently post-prandial. In fact, meals tend to be consumed before the lipids and lipoproteins from the preceding meal are fully metabolized and cleared from the circulation. Consequently, we are exposed to much higher levels of RLPs and in a more persistent manner than what is suggested by the results of studies using fasting lipid samples. This would be especially true of patients afflicted with IR or established DM. As found in adults, RLPs are elevated in obese children and adolescents.9
Whether triglycerides constitute an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) is controversial. A number of investigations suggest that they are, though much depends on covariate adjustment.10-13 The suggestion that RLPs contribute to atherogenesis was first made by Zilversmit in 1979.14 Remnants correlate significantly with risk for CV events. In the Framingham Offspring Study, serum levels of RLPs correlate with risk for CV events in women with established coronary artery disease (CAD).15 Similarly in the Honolulu Heart Study, serum levels of RLPs were significantly associated with risk for CV events among men of Asian descent.16 In the ACCORD trial, RLPs correlated with CV events among diabetic women in a postprandial substudy.17 Remnant levels correlate with risk for acute CV events in Japanese patients with established coronary artery disease (CAD),18 carotid intima media thickness,19 carotid plaque macrophage density,20 ischemic stroke,21 endothelial dysfunction22, and can be extracted from atherosclerotic plaque.23 Among patients with Fredrickson type III dyslipoproteinemia (familial dysbetalipoproteinemia; due to defective apoE), serum remnants are increased leading to the development of xanthomas and elevated risk for CV events.24 More recently, we have demonstrated that increased serum levels of RLPs (defined as sum of VLDL3+IDL) are highly associated with risk for CV events in both the Framingham Heart Study, the Jackson Heart Study, and a meta-analysis performed of both cohorts (HR 1.23; 95% CI 1.06-1.42, p=0.006).25 There was no heterogeneity between cohorts. Thus, RLPs are similarly correlated with CV events in both Caucasians and African Americans.
The RLPs are larger than LDL particles and it has been assumed that their penetration into arterial walls would be limited from biophysical considerations alone. However, both apoB100 and apoB48 can be extracted from atherosclerotic plaque.26 During atherogenesis, LDL particles are oxidatively modified. Oxidation by-products contained within the LDL then induce the expression of scavenging receptors (SR-A, CD-36) on the surface of macrophages to initiate lipid uptake and the formation of macrophage-derived foam cells. The latter step can apparently be bypassed with RLPs.27 RLPs that transcytose into the subendothelial space can egress from the vessel wall via the vasa vasora. However, if the vessel is inflamed and an atherogenic milieu is established, there is increased intercellular matrix material deposited in the subendothelial space, which can trap RLPs. The RLPs do not require oxidative modification in order to be scavenged by macrophages because the macrophages recognize apoE on the surface of these lipoproteins, triggering lipoprotein uptake. Hence, it is biologically plausible that RLPs are in fact atherogenic.
The statins do not impact RLP formation and clearance to a significant degree. The fibrates and high-dose omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acids, i.e., the fish oils) both reduce VLDL secretion and promote the conversion of VLDL to LDL by activating LL.28 Aerobic exercise, weight loss, and smoking cessation all correlate with reductions in RLPs because each of these lifestyle interventions reduces IR. In patients with elevated RLP levels, it is important to reduce intake of saturated fats and increase use of monounsaturated and polyunsaturated fats.
In an indirect way, RLPs were treated under the rubric of non-HDL-C by the Third Adult Treatment Panel.1 However, treatment thresholds and targets for LDL-C and non-HDL-C have been eliminated and replaced by a risk benefit model of care, wherein the intensity of statin therapy is determined by 10 year projected risk.29 The guidelines in Europe and Canada will not be changed in response to the ACC/AHA blood cholesterol treatment guideline. Consequently, there will be disparities in the degree to which RLPs are lowered and how they will (at least indirectly) be targeted for treatment. It is clear that considerable research needs to be done in establishing optimal therapeutic approaches for managing mixed dyslipidemias which include elevations in RLPs. Additional clinical trials will have to be designed that specifically enroll patients with elevated triglycerides and RLPs to help better ascertain the impact of specific therapies CV endpoints. This will make for an important and fascinating new chapter in cardiovascular medicine.
- Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
- Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
- Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E, Mancini GB, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol 2009;25:567-79.
- Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch KM, DeMicco DA, Zwinderman AH, Clearfield MB, Downs JR, Tonkin AM, Colhoun HM, Gotto AM, Jr., Ridker PM, Kastelein JJ. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302-9.
- Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Jr., Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52.
- Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 2006;47:1093-100.
- Bays HE, Toth PP, Kris-Etherton PM, Abate N, Aronne LJ, Brown WV, Gonzalez-Campoy JM, Jones SR, Kumar R, La Forge R, Samuel VT. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:304-83.
- Toth PP, Barter PJ, Rosenson RS, Boden WE, Chapman MJ, Cuchel M, D'Agostino RB, Sr., Davidson MH, Davidson WS, Heinecke JW, Karas RH, Kontush A, Krauss RM, Miller M, Rader DJ. High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:484-525.
- Choi YJ, Jo YE, Kim YK, Ahn SM, Jung SH, Kim HJ, Chung YS, Lee KW, Kim DJ. High plasma concentration of remnant lipoprotein cholesterol in obese children and adolescents. Diabetes Care 2006;29:2305-10.
- Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992;70:3H-9H.
- Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724-30.
- Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S, American Heart Association Clinical Lipidology T, Prevention Committee of the Council on Nutrition PA, Metabolism, Council on Arteriosclerosis T, Vascular B, Council on Cardiovascular N, Council on the Kidney in Cardiovascular D. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
- Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A, Watts GF. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
- Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473-85.
- McNamara JR, Shah PK, Nakajima K, Cupples LA, Wilson PW, Ordovas JM, Schaefer EJ. Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis 2001;154:229-36.
- Imke C, Rodriguez BL, Grove JS, McNamara JR, Waslien C, Katz AR, Willcox B, Yano K, Curb JD. Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart study. Arterioscler Thromb Vasc Biol 2005;25:1718-22.
- Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Jr., Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
- Kugiyama K, Doi H, Takazoe K, Kawano H, Soejima H, Mizuno Y, Tsunoda R, Sakamoto T, Nakano T, Nakajima K, Ogawa H, Sugiyama S, Yoshimura M, Yasue H. Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Circulation 1999;99:2858-60.
- Karpe F, Boquist S, Tang R, Bond GM, de Faire U, Hamsten A. Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. J Lipid Res 2001;42:17-21.
- Zambon A, Puato M, Faggin E, Grego F, Rattazzi M, Pauletto P. Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: a flag for non-HDL-C. Atherosclerosis 2013;230:106-9.
- Kim JY, Park JH, Jeong SW, Schellingerhout D, Park JE, Lee DK, Choi WJ, Chae SL, Kim DE. High levels of remnant lipoprotein cholesterol is a risk factor for large artery atherosclerotic stroke. J Clin Neurol 2011;7:203-9.
- Maggi FM, Raselli S, Grigore L, Redaelli L, Fantappie S, Catapano AL. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. J Clin Endocrinol Metab 2004;89:2946-50.
- Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, Kotite L, Kunitake ST, Havel RJ, Kane JP. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb 1994;14:1767-74.
- Vermeer BJ, Frants RR, Havekes LM. Familial dysbetalipoproteinemia: a genetically heterogenous disease caused by mutations of the ligand apolipoprotein E. J Invest Dermatol 1992;98(6 Suppl):57S-60S.
- Toth PP, Massaro J, Jones S, Griswold M, Lirette S, Martin S, Joshi P, D'Agostino R. Abstract 14026: Remnant Lipoprotein Cholesterol Fractions and Risk for Cardiovascular Events in the Jackson Heart and Framingham Offspring Studies: A Meta-Analysis. Circulation 2013;128(22 Supplement):A14026.
- Proctor SD, Mamo JC. Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol 2003;23:1595-600.
- Fujioka Y, Ishikawa Y. Remnant lipoproteins as strong key particles to atherogenesis. J Atheroscler Thromb 2009;16:145-54.
- Toth PP, Dayspring TD, Pokrywka GS. Drug therapy for hypertriglyceridemia: fibrates and omega-3 fatty acids. Curr Atheroscler Rep 2009;11:71-9.
- Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; [Epub Ahead of Print].
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