Cholesterol, triglycerides, and high-density lipoproteins are important constituents of The lipid transport system in plasma has been described as involving two Subclass HDL2 has been reported to have a better correlation with coronary. High Density Lipoproteins and Reverse Cholesterol Transport . Surprisingly, studies have failed to clearly identify the relationship between. Cholesterol is the most abundant steroid in animals; it is also classified as a. STEROL Lipoproteins function in the blood plasma as transport vehicles for TAGs.
Basic Science Plasma lipoprotein particles contain variable proportions of four major elements: The varying composition of these elements determines the density, size, and electrophoretic mobility of each particle.
These factors in turn have been used for the clinical and biochemical classification of lipoprotein disorders. Schematically, lipoproteins have been described as globular or spherical units in which a nonpolar core lipid consisting mainly of cholesterol esters and triglycerides is surrounded by a layer containing phospholipids, apoproteins, and small amounts of unesterified cholesterol.
Apoproteins, in addition to serving as carrier proteins, have other important functions such as being co-factors for enzymes involved in lipoprotein metabolism, acting as specific ligands for binding of the particles to cellular receptor sites, and intervening in the exchange of lipid constituents between lipoprotein particles.Cholesterol Metabolism, LDL, HDL and other Lipoproteins, Animation
The fact that all the cholesterol required by the body can be produced by biosynthesis points to the essential nature of this substance. As an estimated loss of 1.
Usually this replacement is obtained from dietary sources, but another portion is synthesized in multiple cells of the body. Triglycerides are also obtained from the diet as well as synthesized by the liver. The origin of circulating lipoproteins is less understood than is their uptake, transport, and degradation. The lipid transport system in plasma has been described as involving two pathways: Exogenous and endogenous fat-transport pathways are diagrammed.
Dietary cholesterol is absorbed through the wall of the intestine and is packaged, along with triglyceride glycerol ester-linked to three fatty acid chainsin chylomicrons. In the capillaries more Exogenous Pathway The exogenous pathway starts with the intestinal absorption of triglycerides and cholesterol from dietary sources. Its end result is the transfer of triglycerides to adipose and muscle tissue and of cholesterol to the liver.
After absorption, triglycerides and cholesterol are re-esterified in the intestinal mucosal cells and then coupled with various apoproteins, phospholipids, and unesterified cholesterol into lipoprotein particles called chylomicrons. The chylomicrons in turn are secreted into intestinal lymph, enter the bloodstream through the thoracic: At these binding sites the chylomicrons interact with the enzyme lipoprotein lipase, which causes hydrolysis of the triglyceride core and liberation of free fatty acids.
These fatty acids then pass through the capillary endothelial cells and reach the adipocytes and skeletal muscle cells for storage or oxidation, respectively. After removal of the triglyceride core, remnant chylomicron particles are formed. These remnants are cleared from the circulation by binding of their E apoprotein to a receptor present only on the surface of hepatic cells.
Subsequently, the bound remnants are taken to the inside of hepatic cells by endocytosis and then catabolized by lysosomes. This process liberates cholesterol, which is then either converted into bile acids, excreted in bile, or incorporated into lipoproteins originated in the liver VLDL. Under normal physiologic conditions, chylomicrons are present in plasma for 1 to 5 hours after a meal and may give it a milky appearance.
They are usually cleared from the circulation after a hour fast. Endogenous Pathway The liver constantly synthesizes triglycerides by utilizing as substrates free fatty acids and carbohydrates; these endogenous triglycerides are secreted into the circulation in the core of very-low-density lipoprotein particles VLDL. The synthesis and secretion of VLDL at cellular level occur in a process similar to that of chylomicrons, except that a different B apoprotein B instead of B together with apoproteins C and E intervene in their secretion.
Subsequent interaction of the VLDL particles with lipoprotein lipase in tissue capillaries leads to hydrolysis of the core triglycerides and production of smaller remnant VLDL particles rich in cholesterol esters intermediate-density lipoproteins, IDL and liberation of free fatty acids.
After Apo A-I is secreted, it acquires cholesterol and phospholipids that are effluxed from hepatocytes and enterocytes. While initially cholesterol and phospholipids are obtained from the liver and intestine, HDL also acquires lipid from other tissues and from other lipoproteins. Muscle cells, adipocytes, and other tissues express ABCA1 and are able to transfer cholesterol and phospholipids to lipid poor Apo A-I particles.
This accounts for the observation that patients with high plasma triglyceride levels due to decreased clearance frequently have low HDL cholesterol levels. Finally, the lipolysis of triglyceride rich lipoproteins also results in the transfer of apolipoproteins from these particles to HDL.
The cholesterol that is effluxed from cells to HDL is free cholesterol and is localized to the surface of HDL particles. In order to form mature large spherical HDL particles with a core of cholesterol esters the free cholesterol transferred from cells to the surface of HDL particles must be esterified.
LCAT, an HDL associated enzyme catalyzes the transfer of a fatty acid from phospholipids to free cholesterol resulting in the formation of cholesterol esters. The cholesterol ester formed is then able to move from the surface of the HDL particle to the core. The cholesterol ester carried in the core of HDL particles may be transferred to Apo B containing particles in exchange for triglyceride. Hepatic lipase hydrolyzes both triglycerides and phospholipids in HDL.
Genetic deficiency of hepatic lipase results in a modest elevation in HDL cholesterol levels and larger HDL particles. Hepatic lipase activity is increased in insulin resistant states and this is associated with reduced HDL cholesterol levels. Endothelial cell lipase is a phospholipase that hydrolyzes the phospholipids carried in HDL particles. In mice increased endothelial lipase activity results in decreased HDL cholesterol levels while decreased endothelial lipase activity increases HDL cholesterol levels.
The cholesterol carried on HDL is primarily delivered to the liver. A smaller cholesterol depleted HDL particle is formed, which is then released back into the circulation.
Notably, while HDL cholesterol levels are increased in SR-B1 deficient mice the reverse cholesterol transport pathway is actually reduced. While in mice the physiological importance of the hepatic SR-BI pathway is clear, the role in humans is uncertain.
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In mice, the movement of cholesterol from peripheral tissues to the liver is dependent solely on SR-BI while in humans CETP can facilitate the transport of cholesterol from HDL to Apo B containing lipoproteins, which serves as an alternative pathway for the transport cholesterol to the liver. Most of the Apo A-I is catabolized by the kidneys with the remainder catabolized by the liver. Lipid free or lipid poor Apo A-I is filtered by the kidneys and then taken up by the renal tubules.
The size of the Apo A-I particle determines whether it can be filtered by the kidneys and hence the degree of lipidation of Apo A-I determines the rate of catabolism. Apo A-I binds to cubilin, which in conjunction with megalin, a member of the LDL receptor gene family, leads to the uptake and degradation of filtered Apo A-I by renal tubular cells. While the liver is also involved in the catabolism of Apo A-I, the mechanisms are poorly understood.
Reverse Cholesterol Transport Peripheral cells accumulate cholesterol through the uptake of circulating lipoproteins and de novo cholesterol synthesis. Most cells do not have a mechanism for catabolizing cholesterol. Cells that synthesize steroid hormones can convert cholesterol to glucocorticoids, estrogen, testosterone, etc.
Intestinal cells, sebocytes, and keratinocytes can secrete cholesterol into the intestinal lumen or onto the skin surface thereby eliminating cholesterol. However, in order for most cells to decrease their cholesterol content reverse cholesterol transport is required. From a clinical point of view, the ability of macrophages to efficiently efflux cholesterol into the reverse cholesterol transport pathway may play an important role in the prevention of atherosclerosis.
Additionally, passive diffusion of cholesterol from the plasma membrane to HDL may also contribute to cholesterol efflux. LXR is a nuclear hormone transcription factor that is activated by oxysterols. Cholesterol Efflux from Macrophages modified from J. After the delivery of cholesterol to the liver there are several pathways by which the cholesterol can be eliminated.
Cholesterol can be converted to bile acids and secreted in the bile. Alternatively, cholesterol can be directly secreted into the bile. Thus, an increase in hepatic cholesterol levels leading to increased oxysterol production will activate LXR resulting in the increased expression of ABCG5 and ABCG8 facilitating the secretion of cholesterol in the bile.
Evidence suggests that reverse cholesterol transport plays an important role in protecting from the development of atherosclerosis. It should be noted that HDL cholesterol levels may not be indicative of the rate of reverse cholesterol transport.
As described above reverse cholesterol transport involves several steps and the level of HDL cholesterol may not accurately reflect these steps. For example, studies have shown that the ability of HDL to promote cholesterol efflux from macrophages can vary. Thus, the same level of HDL cholesterol may not have equivalent abilities to mediate the initial step of reverse cholesterol transport.
Lp a contain Apo a and Apo B in a 1: Like Apo B, apo a is also made by hepatocytes. Apo a contains multiple kringle motifs that are similar to the kringle repeats in plasminogen. The number of kringle repeats can vary and thus the molecular weight of apo a can range fromtoLp a levels largely reflect Lp a production rates, which are primarily genetically regulated.
Individuals with high molecular weight Apo a proteins tend to have lower levels of Lp a while individuals with low molecular weight Apo a tend to have higher levels.
It is hypothesized that the liver is less efficient in secreting high molecular weight Apo a. The mechanism of Lp a clearance is uncertain but does not appear to involve LDL receptors. Elevated plasma Lp a levels are associated with an increased risk of atherosclerosis. The kidney appears to play an important role in Lp a clearance as kidney disease is associated with delayed clearance and elevations in Lp a levels.
Journal of lipid research. Apolipoprotein A5 fifteen years anniversary: Lessons from genetic epidemiology. New findings related to genetics, biochemistry, and role in triglyceride metabolism. Taskinen MR, Boren J.
Lipoproteins, cholesterol homeostasis and cardiac health
Journal of molecular medicine. Nordestgaard BG, Langsted A. Lipoprotein a as a cause of cardiovascular disease: Arteriosclerosis, thrombosis, and vascular biology. Protein sensors for membrane sterols.
News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1. Current opinion in lipidology. Wang S, Smith JD. Additionally, excess cholesterol from cells is brought back to the liver by HDL in a process known as reverse cholesterol transport green pathway. It travels in the circulation where it gathers cholesterol to form mature HDL, which then returns the cholesterol to the liver via various pathways.
Disorders and Drug Treatments The link between cholesterol and heart disease was recognized through the study of individuals with familial hypercholesterolemia.
Individuals with this disorder have several-fold higher levels of circulating LDL due to a defect in the function of their LDL receptors. As well, because cholesterol cannot get into cells efficiently, there is no negative feedback suppression of cholesterol synthesis in the liver.
Individuals with familial hypercholesterolemia may have strokes and heart attacks starting in their 30's. More common in the general population is dyslipidemia, which is the term that is used if lipid levels are outside the normal range. In a typical lipid profile, the fasting levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides are determined.
Low levels of HDL cholesterol the so-called "good cholesterol" are an independent risk factor, because reverse cholesterol transport works to prevent plaque formation, or may even cause regression of plaques once they have formed. HDL may also have anti-inflammatory properties that help reduce the risk of atherosclerosis.
Fasting triglyceride levels are used to estimate the level of VLDL. High levels of triglycerides are also associated with an increased risk for atherosclerosis, although the mechanism is not entirely clear. The most important drugs for the treatment of dyslipidemia are by far, the statins. Statins have been shown in multiple clinical trials to reduce cardiovascular events and mortality. Inhibition of cholesterol synthesis further decreases circulating LDL because reduced levels of cholesterol in the hepatocyte cause it to upregulate expression of LDL receptors.
In the past, several different drugs have been used to treat dyslipidemia, however the most recent treatment guidelines recommend mainly statin therapy at different intensities according to the patient's risk for cardiovascular disease.
However, statins may cause adverse effects in some patients, or in others, statins by themselves may not provide sufficient lowering of LDL cholesterol. These patients may benefit from the use of the other two drugs listed below. Two PCSK9 inhibitor drugs were approved in