Apolipoproteins, friends or foes?

 
Professor of Cardiovascular Disease Prevention, Department of Nutrition
Harvard School of Public Health; and Professor of Medicine, Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA

Like cholesterol which circulates in blood located in VLDL, LDL, and HDL, apolipoproteins are found on each lipoprotein. Which is more important to atherosclerosis and coronary heart disease, cholesterol or apolipo - proteins? And, which apolipoproteins are harmful or helpful? The second question is much easier to answer than the first, although the literature is approaching a consensus that apolipoproteins are somewhat better predictors than cholesterol of coronary risk.

Since cholesterol and triglyceride are intensely hydrophobic lipids that do not disperse or dissolve in the aqueous environment of blood plasma, they must be packaged and trans - ported in blood within amphipathic generally spherical “packets” of protein and lipid, called “lipoproteins” (Figure 1).

Figure 1. Small apolipoproteins modulate the metabolism of VLDL an LDL.

The lipoprotein system is conventionally classified by density, mostly a function of triglyceride and cholesterol ester content in the core of the particle and that is directly correlated with flotation rate in water: the more lipid, the faster and easier it floats. Generally, lipid content determines size of the lipoproteins. Quite clearly cholesterol has to be considered an atherogenic molecule since it is the hallmark of atherosclerotic plaque, and indeed cholesterol is linked both mechanistically, epidemiologically, and therapeutically with disease. Cholesterol in the atherogenic lipo - proteins, VLDL and LDL, reflects the cho les terol that is potentially going into the vascular intima, whereas cholesterol in the anti-athero genic lipoprotein, HDL, indicates that which is potentially removable from plaque.

Apolipoproteins B and A-I

The surface of the lipoproteins contains the apolipoproteins notable for their hydrophilic and hydrophobic domains. Atherogenic and antiatherogenic ipoproteins each have a unique
apolipoprotein required for their assembly in the liver and secretion into blood, apolipoprotein B for VLDL and LDL, and apolipoprotein A-I for HDL.In fact, the lipoproteins can be classified according to these principal apolipoproteins, apoB lipo proteins and apoA-I lipoproteins, as advocated for 40 years by Petar Alaupovic.1

This view is gain ing credence from several lines of investigation.2 Apolipoprotein B, in addition to its necessity for lipoprotein structure, has domains for proteo glycan binding that assist delivery of VLDL and LDL to vascular intima and retention in plaque. Apolipoprotein A-I on HDL activates re verse cholesterol transport. Thus the apolipo pro teins directly participate in hostile and friendly roles in atherosclerosis development and healing.

Recent epidemiological studies are showing that apoB is a stronger predictor than cholesterol, either total, nonHDL, or LDL, of coronary events (Figure 2).3

Figure 2. ApoB versus nonHDL-cholesterol (r = 0,93) predict CHD in US health professionals in 18,255 men.(Adapted from reference 3).

Mechanistically, this may be interpreted as the apoB protein providing a more critical interaction to deliver cholesterol to the vessel wall than the amount of cholesterol, per se, that it contains. Although apoA-I has not necessarily been shown to be a stronger predictor than HDL-cholesterol, the ratio of apoB to apoA-I is the single most important and powerful measurement of the lipoprotein system for risk prediction.4

Advantages of an apolipoprotein-based system include its superiority for risk prediction, no need for fasting since meals do not materially alter apoB and apoA-I concentrations, and no need for computation of the principal target, as is needed for LDL-cholesterol. Although in past years, apolipoprotein measurements were not as precise or standardized for accuracy as cholesterol measurements, now we have exceedingly good methodology for apolipoproteins.

Apolipoprotein C-III, a small protein that modulates lipid metabolism and atherogenicity

ApoC-III is a small protein secreted with TG-rich lipoproteins. ApoC-III slows the clearance from plasma of VLDL and its partially metabolized LDL-size remnants by interfering with apoB and apoE binding to LDL receptors on the liver and other tissues.5,6 The blood concentration of VLDL and especially LDL that carry apoCIII is strongly predictive of coronary events and progression of atherosclerosis (Figure 3).7

Figure 3. LDL particles with ApoC-III: strongest risk of recurrent cardiovascular events in diabetes: CARE trial.(Adapted from reference 7).

In fact, apoC-IIIcontaining VLDL or LDL is predictive even when plasma total apoB is included in risk prediction. ApoC-III has other newly recognized properties as a direct player in inflammation and atherogenesis which may account for its exceptionally strong prediction of coronary events. ApoC-III stimulates the recruitment of blood monocytes to vascular endothelial cells by activating adhesion molecules on both cell types.8 ApoC-III activates major transcription factors that mediate inflammation, including nuclear factor kappa B and protein kinase C alpha and beta. Since apoC-III occurs exclusively on TG-rich apoB lipoproteins, we may have not only a new marker for the risk of atherogenic dyslipidaemia but one that indicates direct atherogenic, pro-inflammatory actions (Figure 4).

Figure 4. ApoC-III in VLDL and LDL causes monocytic celle adhesion to endothelial cells. (Adapted from reference 8).

ApoC-III is also on HDL where it may reduce HDL’s anti-atherogenic actions. However, we
have limited information on what apoC-III does on HDL.

In summary, apoB and apoA-I are the “foe” and “friend” among apolipoproteins for vascular
health. But they do not fully tell the story of hypertriglyceridaemia and atherogenic dyslipidaemia and residual CVD risk. To do this, markers of atherogenicity of TG-rich lipoproteins will be needed to be validated in many populations, and convenient methodology developed for their precise and accurate quantifying. Among these measures, apoC-III has multiple levels of research support, from epidemiology to metabolism to cell biology, and its presence on partially metabolized apoB lipoproteins may be the best indicator of the growing risk associated with metabolic syndrome, risk that often remains in patients optimally treated for cholesterol targets. Perhaps apoC-III will be a marker of dysfunctional, pro-inflammatory apoB, and apoA-I (HDL) lipoproteins in atherogenic dyslipidaemia and metabolic syndrome.

References

1. Alaupovic P. Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins. Methods Enzymol 1996;263:32-60.
2. Sacks FM. The apolipoprotein story. Atheroscler Suppl 2006;7:23-7.
3. Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005;112:3375-83.
4. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.
5. Clavey V, Lestavel-Delattre S, Copin C, et al. Modulation of lipoprotein B binding to the LDL receptor by exogenous lipids and apolipoproteins CI, CII, CIII, and E. Arterioscler Thromb Vasc Biol 1995;15:963-71.
6. Zheng C, Khoo C, Ikewaki K, Sacks FM. Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions. J Lipid Res 2007;48:1190-203.
7. Lee SJ, Campos H, Moye LA, Sacks FM. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler Thromb Vasc Biol 2003;23:853-8.
8. Kawakami A, Aikawa M, Libby P, et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation 2006;113:691-700.