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.

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Keywords: Apoproteins, Atherosclerosis, Cholesterol, Cholesterol Esters, Cholesterol, LDL, Lipids, Lipoprotein(a), Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, HDL2, Lipoproteins, VLDL, Lipoproteins, IDL, Lipoproteins, Membrane Fluidity, Muscle, Skeletal, Myocardium, Phospholipids, Triglycerides, Secondary Prevention

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