LIPOPROTEINS
Introduction
Lipids (for example, cholesterol) are a type of biomolecule which are only sparingly soluble in aqueous solutions. Therefore, they cannot be transported through the cardiovascular system as free molecules since this insolubility would block the blood vessels. Hence, the insoluble lipids assemble with phospholipids and proteins to form spherical complexes known as lipoproteins. There are multiple classes of lipoproteins with different structures. In order to change forms, a lipoprotein must undergo a series of complex metabolic processes in which exchanges between the various lipoproteins and organs take place. This process is referred to as the lipoprotein cascade.
What Are Lipoproteins?
Structure
Lipoproteins are composed of lipids complexed with apolipoproteins forming a micellular structure. The lipoprotein core is hydrophobic (water insoluble) as it contains triacylglycerides and cholesterol esters, while the surface is hydrophilic (water soluble) as it is made of amphipathic molecules including cholesterol, phospholipids and apoproteins. This allows the lipoproteins to be transported in the aqueous blood plasma. There are 5 classes of lipoproteins each with their own distinct compositions/ratios of insoluble lipids and soluble proteins.
There are 5 classes of lipoproteins:
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Chylomicrons
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Very low density lipoproteins (VLDLs)
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Low density lipoproteins (LDLs)
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Intermediate density lipoproteins (IDLs)
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High density lipoproteins (HDLs)
Figure 1: A graphical representation of the different lipoproteins and their composition:
Function
Lipoproteins have multiple important roles in the body. One such role involves lipid transport. As lipids are sparingly insoluble in aqueous solution, they cannot be transported in the blood or lymph as free molecules hence, these are complexed with apoproteins to form lipoproteins which can be safely transported. However, in humans, lipid transportation leads to gradual deposition of lipids, especially cholesterol, which results in plaque formation which can subsequently cause atherosclerosis. In addition, lipoproteins participate in cholesterol and triacylglycerol metabolism. Furthermore, lipoproteins possess signals that regulate movement of particular lipids in and out of cells. These signals are brought about by the different apoproteins present on different types of lipoproteins.
Diet
The lipoprotein profile (which shows the quantities of different lipoproteins in the body) impacts health and is affected by food intake. A diet high in saturated fats leads to an elevated blood cholesterol level which in turn can lead to blood vessel blockage (ex. heart attack). If a person consumes a significant amount of fish oils, which are rich in Omega E unsaturated fats, the blood cholesterol and triglyceride levels decrease. Monounsaturated and polyunsaturated fatty acids that are found in foods such as olive oil, peanut and sunflower oils also reduce blood cholesterol.
Figure 1
Lipoprotein Metabolism:
Triacylglceride breakdown starts within the small intestine, producing monoacylglycerides and free fatty acids. The products of this reaction then move into enterocyte cells where they enter the smooth endoplasmic reticulum and are packaged to form chylomicrons. The chylomicrons formed also contain cholesterol, this is metabolised with the TAGs (triacylglycerides) during the lipoprotein cascade.
Next, chylomicrons move into the circulatory system via thoracic ducts. In blood vessels the chylomicrons come into contact with HDL which transfers proteins that allow the chylomicron to bind to lipoprotein lipase (LPL) receptors on the surface of the blood vessels. This causes the chylomicrons to break down forming free fatty acids (FFAs) and glycerol. The FFAs are then used to produce ATP which provides a source of energy or TAGs which provide a stored source of energy. The remnant chylomicron is then transported to the liver where it is broken down and its contents are either stored within the liver itself or used to form VLDLs. These contain more cholesterol and less TAGs than their precursors.
The VLDLs re-enter the bloodstream where HDL donates its proteins again to allow the VLDL to bind to LPL receptors. This once again releases FFAs and glycerol which are used to produce or store energy. Loss of FFAs and glycerol forms IDL, the VLDL remnant. This step ends the exogenous lipid cascade and initiates the endogenous lipid cascade. The IDL formed then moves to the liver or adrenal cortex where it is broken down or used to produce corticoid hormones via the donation of FFAs, glycerol, or cholesterol. This results in the formation of an IDL remnant which moves back into the blood vessels. Here, it returns the protein initially given to it by HDL and forms LDL which contains a high percentage of cholesterol. LDL may deposit this cholesterol at the sex organs, adrenal cortex or liver.
The liver is the preferred destination of the LDL and it is where it is broken down to produce new components which are used to create new lipoproteins. LDL build-up in these vessels is the cause of atherosclerosis which is prevented using ABCA1 and ABCG1 proteins that reduce cholesterol from HDL by allowing its release. This cholesterol release forms mature HDL which is able to transfer its remaining cholesterol to the other types of lipoproteins whilst itself receiving TAGs from them.
Both TAGs and cholesterol are metabolised via the lipoprotein cascade. This occurs by the release of the two from within lipoproteins into areas which require them for production. TAGs are released from lipoproteins upon their binding to LPL receptors whilst cholesterol requires LRP (lipoprotein receptor-related protein) receptors to be released.
See Figure 2 in the Images section for a graphical representation of lipoprotein metabolism
Figure 2
Figure representing lipoprotein metabolism. Lipoprotein metabolism can be split into 3: Endogenous, exogenous and reverse transport.
Lipoproteins and disease:
Familial Hypercholesterolemia (FH)
Familial hypercholesterolaemia is a condition defined as a level of LDL‑C exceeding a cut-off point determined by national guidelines as conferring increased risk of cardiovascular disease (CVD). FH is a hereditary disease meaning that individuals with FH typically have mutations affecting their LDL receptor which can be inherited by their offspring. The result of these mutations is a higher than normal level of serum cholesterol. Individuals with the rare homozygous form (1 in a million) have grossly elevated levels of serum cholesterol (16-25mmol/l) and usually die of heart disease before the age of 20. People heterozygous to the disease (1 in 500) have relatively high levels of serum cholesterol (6.5-13mmol/l) and are at high risk for heart attacks. In Westernized countries it is by far the most prevalent form of elevated LDL‑C. It reflects diet (intake of saturated and trans-unsaturated fats, and obesity) and multiple genetic determinants including the Apo E4 gene. It is a clinically important subset of the primary causes of this lipoprotein pattern (elevated LDL‑C) and is itself composed of several subsets. In FH, there is also an autosomal recessive form (ARH) attributable to defects in the function of a chaperone protein. Mutations affecting the receptor binding region of the apo-B100 receptor ligand cause a less severe dominantly inherited clinical syndrome known as familial defective Apo B (FDB).
Another subgroup is due to a gain-of-function mutation of the PCSK9 gene, which tends to cause a relatively severe clinical picture. The risk of cardiovascular disease is related to plasma levels of total cholesterol and LDL-cholesterol. The desirable level of LDL appears to be below 305 mmol/L. The risk of cardiovascular disease increases when the total cholesterol level is above 6 mmol/l.
Treatment options:
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Dietary restriction of cholesterol to less than 300 mg/day, restriction of total fat intake to less than 30% of total calories.
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The administration of bile salt-binding drugs such as cholestyramine and colestipol. These drugs promote excretion of bile salts in the stool. This in turn increases the synthesis of hepatic bile salt synthesis and of LDL uptake by the liver.
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Drugs called statins are used as treatment which work by inhibiting cholesterol synthesis. An example of a statin is Lovastatin. Lovastatin is an inhibitor of HMG-CoA reductase, therefore decreases endogenous synthesis of cholesterol and stimulates uptake of LDL via the LDL receptor.
Diabetes & Coronary Heart Disease
According to Athyros et al. (2018), insulin resistance is prevalent in obese individuals, partly due to the elevated amount of free fatty acids in the blood. Elevated free fatty acids contribute to several effects: they inhibit glucose degradation in tissues such as muscle, they interfere with the insulin-stimulated transport of glucose into muscle by blocking GLUT4 glucose transporter, they stimulate gluconeogenesis in the liver, may inhibit transcription of insulin, and may bind to and inhibit the insulin receptor.
According to Freeman (2006) atherosclerosis is the process by which atherosclerotic plaques form. The key event in early atherosclerosis is damage to the endothelium which may be caused by oxidised LDLs, hypertension and cigarette smoking. Then, LDL penetrates the vascular wall and deposit in the intima where they undergo oxidation. The presence of oxidized LDL attracts monocytes to the arterial wall. Monocytes enter the arterial wall and transform into macrophages. These macrophages are immobilised in the subendothelial space. The oxidized Apo B100 can no longer bind to the LDL receptor.
The oxidized LDL is engulfed by the macrophage via the scavenger receptor. Since the scavenger receptor is not regulated, the cells become overloaded with lipid and become foam cells. Conglomerates of foam cells form streaky yellow patches visible in the arterial wall. Dying foam cells release lipids that form pools within the arterial wall.
The surrounding smooth muscle cells and endothelial cells secrete cell growth regulators such as cytokines, growth factor, interleukin-1 and tumour necrosis factor. These peptides stimulate smooth muscle cells to proliferate and to migrate towards the lumen side of the arterial wall. At this time the smooth muscle cells start secreting collagen. This results in the formation of a cap that covers the lipid pool which forms the mature atherosclerotic plaque.
Hypertriglyceridemia
Hypertriglyceridemia is a condition which is caused by very high levels of chylomicrons and VLDLs which then leads to high levels of triglycerides in the blood. This condition is mostly caused by excess intake of fat or alcohol, obesity and also Type 2 diabetes.
Stroke
Lipoproteins play a role in predicting strokes and also coronary heart disease. There is a link between levels of lipoprotein (a) and plasma fibrinogen, with an increase in the level of fibrinogen in the blood being an indicator of vascular events such as strokes. Lipoproteins also demonstrate protective properties against acute stroke by helping reverse the effects caused when there is a lack of oxygen being supplied to the brain (Meilhac, 2015).
References:
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Athyros, V. G., Doumas, M., Imprialos, K. P., Stavropoulos, K., Georgianou, E., Katsimardou, A., & Karagiannis, A. (2018). Diabetes and lipid metabolism. Hormones (Athens, Greece), 17(1), 61-67.
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Freeman, M. W. (2006). Lipid metabolism and coronary artery disease. In M. S. Runge, & C. Patterson (Eds.), Principles of molecular medicine (pp. 130-137). Totowa, NJ: Humana Press.
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Meilhac O. (2015) High-Density Lipoproteins in Stroke. In: von Eckardstein A., Kardassis D. (eds) High Density Lipoproteins. Handbook of Experimental Pharmacology, vol 224. Springer, Cham. Obtained from: