Elevated levels of certain plasma lipoproteins are associated with an increased risk of cardiovascular disease. Measurements of the levels of these lipoproteins are considered reliable biomarkers for assessing cardiovascular risk by the mainstream medical establishment. However, the nutritional biochemistry of plasma lipoproteins in reality is far more complex than these simplistic clinical models suggest. Further, some evidence suggests that some clinical tests may not be accurately measuring the required parameter because of insensitivity in the assay. The main reason for these problems is that many such tests are based on work performed four or five decades previously and the complexity of lipoprotein biochemistry has advanced considerably since that time. Many new sub-classes of lipoproteins have been identified and characterised in recent years. An understanding of the main metabolic and biochemical effects of lipoproteins is therefore of critical importance.
Transporting lipids in aqueous tissues is problematic for animals because lipids will not dissolve in plasma. The solution is to contain the lipids within a phsopholipid, cholesterol and protein coat (figure 1). Phospholipids are amphiphilic and can arrange themselves to envelop the hydrophobic lipids to the interior. Within the phospholipid envelop sit amphiphilic proteins, that arrange themselves such that their hydrophobic regions interact with the lipids and their hydrophilic regions interact with the surrounding aqueous environment. The proteins on the surface of the lipoproteins are called apolipoproteins and the type can vary between lipoproteins. The outer coat of lipoproteins also contains free (unesterified) cholesterol which has ampliphilic properties. In the lipoprotein interior is contained the cholesteryl esters and triglycerides, both of which are highly lipophilic. Lipoproteins consist of a heterogeneous group of particles and the ratio of cholesterol to triglycerides, their size and protein types can vary.
Figure 1. Generic structure of a lipoprotein.
Lipoproteins can be separated either though their electrophoretic mobility or through ultracentrifugation. The latter technique gives rise to the main lipoprotein classification used in the nutritional sciences. It is important to understand that while lipoproteins can be classified into distinct groups, in reality these groups form a continuous transition from one particle to another. This continuous transition of lipoproteins is a result of the biochemical metabolism of the liporporteins under normal physiological conditions. As the lipoproteins interact with tissues and other lipoproteins, their cholesterol, triglyceride and protein content changes because these components are transferred to tissues and between lipoproteins. This alters their density and sizes along an infinite spectrum depending on their metabolic fate. The classification of the lipoproteins based on ultracentrifugation include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), high density lipoproteins (HDL) and lipoprotein(a) (figure 2).
Figure 2. The structure of the different classes of lipoproteins. Apolipoprotein E may play a role in atherogenesis. Apolipoprotein E is one of the components recognised by the LDL receptor. Apolipoprotein E exists in three isoforms (E2, E3 and E4). Each person inherits one isoform from each parent giving six possible combinations. Evidence suggests that the apolipoprotein E4 variant increases risk for cardiovascular disease. Apolipoprotein E phenotype is associated with a stepwise increase in LDL plasma concentrations, from zero to one to two alleles.
Chylomicrons are involved in the absorption of exogenous dietary lipids. Fatty acids, monoglycerides, and cholesterol absorbed to enterocytes are re-esterified to form triglycerides and cholesteryl esters, and these are packaged into large lipoproteins, where they pass into the circulation via the lymphatic system, ultimately reaching the blood through the subclavian vein. These lipoproteins consist of a core of cholesteryl esters and triglycerides, with a surface of free cholesterol and phospholipids along with the apolipoproteins B48 and A1. In the plasma chylomicrons accumulate apolipoprotein C2 from other lipoprotein particles, and this protein makes them a substrate for lipoprotein lipase in adipose tissue and muscle. As the triglyceride content is hydrolysed, the particle is reduced in size and some of the cholesterol and apolipoproteins are transferred to other lipoproteins, such as HDL. The smaller denser chylomicron remnant containing less triglyceride is taken up by the liver where it is catabolised.
The VLDL particle is the main transport lipoprotein for endogenously produced triglycerides from the liver. The VLDL particles transport triglycerides from the liver to adipose and muscle tissue, where lipoprotein lipase hydrolyses the triglycerides. This is the main way of distributing triglyceride energy from hepatic triglyceride production to the tissues. As VLDL is depleted further of triglycerides, they become relatively enriched in cholesteryl esters and form first the IDL, and then subsequently the LDL particle. The final LDL particle can remain in circulation for some time. Alternatively, the remnant core and surface proteins of VLDL, once depleted of triglycerides can pass to other lipoproteins such as the HDL particle which results in a cholesteryl ester rich lipoprotein. This particle can then be taken up by the LDL receptor in the liver or peripheral tissues, which binds apolipoprotein B100 and apolipoprotein E from the surface.
The LDL particles have a long half life in circulation of around 3 days. They leave the plasma through uptake by the LDL receptor (apolipoprotein B/E receptor) in various tissues. Tissues with an LDL receptor can therefore accumulate cholesterol, which decreases endogenous cholesterol synthesis through inhibition of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme. This process also decreases the synthesis and expression of the LDL receptors and so further uptake of the circulating LDL particles is suppressed. Macrophages possess a receptor called the LDL scavenger receptor, and this receptor is not subject to suppression by excess cholesterol uptake. The macrophages can therefore become laden with cholesterol, which may be associated with the formation of atherosclerotic plaques in the endothelial lining of the artery walls. However, the LDL particle class is divided into small dense and large buoyant sub-types and only the former increases risk for cardiovascular disease.
The HDL particles are created as discoidal lipoproteins in the liver, that consist of phospholipids and apolipoprotein A1. These particles become enriched with cholesteryl esters during the action of lipoprotein lipase on the triglyceride rich chylomicrons and VLDL particles. They also accumulate cholesterol from cells, which is esterified by the action of lecithin-cholesterol acyltansferase, an enzyme activated by apolipoprotein A1. In this enrichment process the discoidal particle become spherical, and this relatively large HDL particle is now called HDL2. Some of the cholesterol esters are taken up by the liver and some are transferred to the triglyceride rich lipoproteins. The deplete HDL particle that results from this process is called the HDL3 particle, which can acquire new cholesterol from the peripheral tissues. The cholesteryl ester transference from the tissues to the liver is called the reverse cholesterol transport, and this cholesterol is excreted as bile.
Lipoprotein(a) [Lp(a)] is a lipoprotein particle that possesses a very similar appearance to the archetypal LDL particle. It is roughly the same size and possesses similar ratios of phospholipids, free cholesterol, cholesteryl esters and triglycerides. However the Lp(a) particle has the addition of a 513, 000 D protein marker referred to as apolipoprotein(a) [apo(a)]. Apolipoprotein(a) links to the B100 surface protein through a disulfide bridge. Lipoprotein(a) is actually a genetic variant of LDL, and levels vary considerably between individuals. Elevated levels of Lp(a) are associated with atherosclerosis, but the physiological function of Lp(a) is not known. Linus Pauling and Matthias Rath have suggested that levels of Lp(a) rise during ascorbate deficiency in order to add structural integrity to the blood vessel walls caused through scorbutic bleeding. In fact Pauling and Rath claim that LDL in early lipoprotein research may have been mistaken for Lp(a).
Circulating in the plasma is a protein called the cholesteryl ester-transfer protein (CETP). The CETP catalyses the transfer of cholesteryl esters and lipids between lipoproteins. This occurs down concentration gradients by facilitated diffusion. For example, in the post absorptive state following a meal, CEPT can facilitate the transfer of cholesteryl esters from HDL particles to chylomicrons. At the same time, triglycerides can be transferred from chylomicrons to HDL particles. The cholesteryl ester in the chylomicron could then be taken up by the liver with the chylomicron remnant for catabolism. In contrast, the triglyceride enriched HDL2 particle could release its cholesteryl esters to the liver leaving a smaller denser HDL3 particle that can pass to the tissues to become enriched with more cholesteryl esters. Therefore enzymatic transfer of lipids between lipoproteins and the hydrolysis of lipids by lipoprotein lipase gives rise to the spectrum of lipoproteins seen in plasma.
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