Cholesterol, lipoproteins and the liver
(You can refresh your memory about the structure of lipoproteins by visiting the The link between cholesterol and heart disease was recognized through the. Cholesterol is a lipid with a unique structure consisting of four fused hydrocarbon . Total cholesterol = LDL cholesterol + HDL cholesterol + VLDL cholesterol. Cholesterol and triglycerides are insoluble in water and therefore these Figure 1: Lipoprotein Structure (figure modified from Biochemistry
These particles are then secreted into the lacteals in a process that depends heavily on apolipoprotein B As they circulate through the lymphatic vesselsnascent chylomicrons bypass the liver circulation and are drained via the thoracic duct into the bloodstream. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate lipoprotein lipase LPLan enzyme on endothelial cells lining the blood vessels.
LPL catalyzes the hydrolysis of triacylglycerol glycerol covalently joined to three fatty acids that ultimately releases glycerol and fatty acids from the chylomicrons.
Glycerol and fatty acids can then be absorbed in peripheral tissues, especially adipose and musclefor energy and storage. The hydrolyzed chylomicrons are now called chylomicron remnants. The chylomicron remnants continue circulating the bloodstream until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the endocytosis of the chylomicron remnants, which are subsequently hydrolyzed within lysosomes.
Lysosomal hydrolysis releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use.
LDL and HDL Cholesterol: "Bad" and "Good" Cholesterol
Endogenous pathway[ edit ] The liver is the central platform for the handling of lipids: Hepatocytes are also able to create triacylglycerols via de novo synthesis. They also produce the bile from cholesterol. The intestines are responsible for absorbing cholesterol. They transfer it over into the blood stream. In the hepatocytestriacylglycerols and cholesteryl esters are assembled with apolipoprotein B to form nascent VLDL particles. Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B As cholesterol levels in the cell decrease, inactive sterol regulatory element binding proteins SREBPswhich are transcription factors that mediate the expression of LDL receptors and other key genes involved in cholesterol and fatty acid metabolism, are transported from the endoplasmic reticulum to the golgi where proteases cleave the SREBPs into active transcription factors Figure 4.
If cholesterol levels in the cell are high, then the SREBPs remain in the endoplasmic reticulum in an inactive form and do not stimulate LDL receptor synthesis. In addition, cholesterol in the cell is oxidized and oxidized sterols activate LXR, a nuclear hormone receptor that is a transcription factor, which stimulates the transcription of E3 ubiquitin ligase that mediates the ubiquitination and degradation of the low-density lipoprotein receptor Inducible degrader of the low-density lipoprotein receptor IDOL.
Thus, the cell can sense the availability of cholesterol and regulate LDL receptor activity. If the cholesterol content of the cell is decreased LDL receptor activity is increased to allow for the increased uptake of cholesterol.
Conversely, if the cholesterol content of the cell is increased LDL receptor activity is decreased and the uptake of LDL by the cell is diminished.
Lipoprotein - Wikipedia
Thus, the endogenous lipoprotein pathway facilitates the movement of triglycerides synthesized in the liver to muscle and adipose tissue. Additionally, it also provides a pathway for the transport of cholesterol from the liver to peripheral tissues. Apo A-I is synthesized predominantly by the liver and intestine. 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.
LDL & HDL: Good & Bad Cholesterol | posavski-obzor.info
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. 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. The health significance is that they are prone to cardiovascular diseases. If a clot forms and blocks the narrowed artery, a series of cardiovascular diseases such as hypertension, myocardial infarction, arteriosclerosis, angina pectoris, heart attack or stroke can result.
High levels of cholesterol are also closely associated to diabetes. HDL is known as "good" cholesterol in that it removes excess cholesterol in the arteries and transport it back to the liver for excretion or re-utilization, and thus preventing the arteries from clogging. Hypocholesterolemia is a condition when there is an extremely low level of cholesterol in the body.
This condition is usually rare, but if they do occur, it might be because of other illness that has caused the body to generate low or no cholesterols.