The particles that package cholesterol, cholesteryl esters, and triglycerides for transport, are called lipoproteins. There are five main classifications of lipoproteins. Cholesterol is insoluble in the blood, it is transported to and from the cells by Low-density lipoprotein (LDL) or “Bad Cholesterol” is the major cholesterol carrier. Cholesterol and triglycerides are insoluble in water and therefore these lipids must be transported in association with proteins. Lipoproteins are.
Each class of lipoproteins is indicated at the top. The amount of each lipoprotein class is proportional to the area under each curve and is shown numerically at the bottom. Three subclasses of HDL are shown. Modified from Fredrickson et al. Lp a is a complex particle in human plasma that is assembled from one LDL molecule that carries all the lipid and one glycoprotein [apo a ], which has a high degree of homology to plasminogen.
Lp a provides some risk for atherosclerosis. Table 1 presents the overall composition of these lipoproteins.
Lipoproteins, cholesterol homeostasis and cardiac health
FFA were discovered in plasma by Szent-Gyorgi and Tominaga in and reinvestigated by Dole and Gordon and Cherkeswho explored their physiologic significance and their binding to albumin. On the basis of physiologic studies of organ function and isotopic studies of lipoprotein turnover, it was concluded that triglycerides are transported by chylomicrons from the gut to adipose tissue, and by VLDL from the liver to adipose tissue.
It was then shown by study of A-V differences that fat transport from adipose tissue to liver and other tissues was accomplished by FFA bound to albumin. Isotopic studies showed that the turnover time of FFA in humans is about 3 min, which means that about g of fatty acids 2—3 times the daily intake is transported by human plasma each 24 h.
Figure 2 View large Download slide The transport of lipid among the organs of the mammal. After internalization, the lipoprotein particle is degraded in lysosomes and the cholesterol is released. The delivery of cholesterol to the cell decreases the activity of HMGCoA reductase, a key enzyme in the biosynthesis of cholesterol, and the expression of LDL receptors.
The number of LDL receptors is regulated by the cholesterol content of the cell 9. When cellular cholesterol levels are decreased the transcription factor SREBP is transported from the endoplasmic reticulum to the golgi where proteases cleave and activate SREBP, which then migrates to the nucleus and stimulates the expression of LDL receptors Figure 4.
Conversely, when cellular cholesterol levels are high SREBP remains in the endoplasmic reticulum in an inactive form and the expression of LDL receptors is low.
It is expressed in multiple tissues including the liver. SR-B1 is expressed in the liver, adrenal glands, ovaries, testes, macrophages, and other cells. In the liver and steroid producing cells, it mediates the selective uptake of cholesterol esters from HDL particles.
Cholesterol, Lipoproteins and the Liver
In macrophages and other cells, it facilitates the efflux of cholesterol from the cell to HDL particles. ABCA1 is expressed in many cells including hepatocytes, enterocytes, and macrophages. ABCG1 is expressed in many different cell types and mediates the efflux of cholesterol from the cell to HDL particles.
In the intestine, these transporters mediate the movement of plant sterols and cholesterol from inside the enterocyte into the intestinal lumen thereby decreasing their absorption and limiting the uptake of dietary plant sterols.
In the liver, these transporters play a role in the movement of cholesterol and plant sterols into the bile facilitating the excretion of plant sterols.
NPC1L1 is expressed in the intestine and mediates the uptake of cholesterol and plant sterols from the intestinal lumen into the enterocyte. Lipoprotein lipase LPL LPL is synthesized in muscle, heart, and adipose tissue, then secreted and attached to the endothelium of the adjacent blood capillaries. This enzyme hydrolyzes the triglycerides carried in chylomicrons and VLDL to fatty acids, which can be taken up by cells.
This enzyme requires Apo C-II as a cofactor. Apo A-V also plays a key role in the activation of this enzyme. Insulin stimulates LPL expression and LPL activity is reduced in patients with poorly controlled diabetes, which can impair the metabolism of triglyceride rich lipoproteins leading to hypertriglyceridemia. Hepatic lipase is localized to the sinusoidal surface of liver cells.
This lipase plays a major role in hydrolyzing the phospholipids in HDL. LCAT is made in the liver. In the plasma, it catalyzes the synthesis of cholesterol esters in HDL by facilitating the transfer of a fatty acid from position 2 of lecithin to cholesterol. This allows for the transfer of the cholesterol from the surface of the HDL particle free cholesterol to the core of the HDL particle cholesterol esterwhich facilitates the continued uptake of free cholesterol by HDL particles by reducing the concentration of cholesterol on the surface of HDL.
Cholesteryl ester transfer protein CETP Exogenous Lipoprotein Pathway Fat Absorption The exogenous lipoprotein pathway starts in the intestine. Dietary triglycerides approximately grams per day are hydrolyzed to free fatty acids and monoacylglycerol by intestinal lipases and emulsified with bile acids, cholesterol, plant sterols, and fat soluble vitamins to form micelles.
While the fatty acids in the intestine are overwhelmingly accounted for by dietary intake the cholesterol in the intestinal lumen is primarily derived from bile approximately mg of cholesterol from bile vs. The cholesterol, plant sterols, fatty acids, monoacylglycerol, and fat soluble vitamins contained in the micelles are then transported into the intestinal cells.
The uptake of cholesterol and plant sterols from the intestinal lumen into intestinal cells is facilitated by a sterol transporter, Niemann-Pick C1- like 1 protein NPC1L1 Figure 6. Ezetimibe, a drug which inhibits intestinal cholesterol and plant sterol uptake, binds to NPC1L1 and inhibits its activity. Once in the intestinal cell the cholesterol and plant sterols may be transported back into the intestinal lumen, a process mediated by ABCG5 and ABCG8, or converted to sterol esters by acyl-CoA cholesterol acyl transferase ACATwhich attaches a fatty acid to the sterol.
Compared to cholesterol, plant sterols are poor substrates for ACAT and therefore the formation of plant sterol esters does not occur as efficiently as the formation of cholesterol esters. Intestinal Cell and Sterol Metabolism The pathway of absorption of free fatty acids is not well understood but it is likely that both passive diffusion and specific transporters play a role.
The fatty acid transporter CD36 is strongly expressed in the proximal third of the intestine and is localized to the villi. While this transporter likely plays a role in fatty acid uptake by intestinal cells, this transporter is not essential as humans and mice deficient in this protein do not have fat malabsorption. However, in mice deficient in CD36 there is a shift in the absorption of lipid to the distal intestine, suggesting pathways that can compensate for the absence of CD Fatty acid transport protein 4 FATP4 is also highly expressed in the intestine.
However, mice deficient in FATP4 do not have abnormalities in fat absorption. The pathways by which monoacylglycerols are absorbed by intestinal cells remain to be defined.
Formation of Chylomicrons 20, 23 The absorbed fatty acids and monoacylglycerols are utilized to synthesize triglycerides. MGAT catalyzes the addition of a fatty acid to monoacylglycerol while DGAT catalyzes the addition of a fatty acid to diacylglycerol resulting in triglyceride formation. As noted above, the majority of the cholesterol absorbed by the intestine is esterified to cholesterol esters by ACAT. The triglycerides and cholesterol esters are packaged into chylomicrons in the endoplasmic reticulum.
The size and composition of the chylomicrons formed in the intestine are dependent on the amount of fat ingested and absorbed by the intestine and the type of fat absorbed. Increased fat absorption results in larger chylomicrons. The formation of chylomicrons in the endoplasmic reticulum requires the synthesis of Apo B by the intestinal cell Figure 6.
Microsomal triglyceride transfer protein MTP is required for the movement of lipid from the endoplasmic reticulum to the Apo B The absence of MTP results in the inability to form chylomicrons Abetalipoproteinemia.
Lomitapide inhibits MTP function and is used to treat patients with homozygous Familial Hypercholesterolemia. Chylomicron Metabolism 4, 5, 15, Chylomicrons are secreted into the lymph and delivered via the thoracic duct to the circulation.
It should be noted that this results in the newly formed chylomicrons being delivered to the systemic circulation and not delivered directly to the liver via the portal circulation. This facilitates the delivery of the nutrients contained in the chylomicrons to muscle and adipose tissue. In muscle and adipose tissue lipoprotein lipase LPL is expressed at high levels. LPL is synthesized in muscle and adipocytes and transported to the luminal surface of capillaries.
Lipoproteins, cholesterol homeostasis and cardiac health
Lipase maturation factor 1 plays a key role in the stabilization and movement of LPL from muscle cells and adipocytes to the capillary endothelial cell surface. Activation of LPL by Apo C-II, carried on the chylomicrons, leads to the hydrolysis of the triglycerides that are carried in the chylomicrons resulting in the formation of free fatty acids, which can be taken up by the adjacent muscle cells and adipocytes for either energy production or storage.
Some of the free fatty acids released from chylomicrons bind to albumin and can be transported to other tissues. In addition, there are proteins that inhibit LPL activity. Loss of function mutations in these proteins also are associated with decreases in plasma triglyceride levels. Finally, the expression of LPL by muscle cells and adipocytes is regulated by hormones particularly insulinnutritional status, and inflammation.
The metabolism of the triglycerides carried in the chylomicrons results in a marked decrease in the size of these particles leading to the formation of chylomicron remnants, which are enriched in cholesterol esters and acquire Apo E.
As these particles decrease in size phospholipids and apolipoproteins Apo A and C on the surface of the chylomicrons are transferred to other lipoproteins, mainly HDL. These chylomicron remnants are cleared from the circulation by the liver. The Apo E on the chylomicron remnants binds to the LDL receptor and other hepatic receptors such as LRP and syndecan-4 and the entire particle is taken up by the hepatocytes.
Apo E is crucial for this process and mutations in Apo E for example the Apo E2 isoform can result in decreased chylomicron clearance and elevations in plasma cholesterol and triglyceride levels Familial dysbetalipoproteinemia. The exogenous lipoprotein pathway results in the efficient transfer of dietary fatty acids to muscle and adipose tissue for energy utilization and storage.
The cholesterol is delivered to the liver where it can be utilized for the formation of VLDL, bile acids, or secreted back to the intestine via secretion into the bile.
In normal individuals, this pathway can handle large amounts of fat grams or more per day without resulting in marked increases in plasma triglyceride levels. In fact, in a normal individual, a meal containing 75 grams of fat results in only a very modest increase in postprandial triglyceride levels. Similar to the intestine this transfer is mediated by MTP. The availability of triglycerides is the primary determinant of the rate of VLDL synthesis.
If the supply of triglyceride is limited the newly synthesized Apo B is rapidly degraded. Thus, in contrast to many proteins the rate of synthesis of the Apo B is not the major determinant of the rate of secretion.
Rather the amount of lipid available determines whether Apo B is degraded or secreted. MTP is required for the early addition of lipid to Apo B particles but additional lipid is added via pathways that do not require MTP. Loss of function mutations in either Apo B or MTP result in the failure to produce VLDL and marked decreases in plasma triglyceride and cholesterol levels Familial hypobetalipoproteinemia or abetalipoproteinemia.
The precise pathway by which the newly synthesized VLDL particles are secreted from the hepatocyte into the circulation is not resolved. This process is very similar to that described above for chylomicrons and there is competition between the metabolism of chylomicrons and VLDL. High levels of chylomicrons can inhibit the clearance of VLDL.
The remaining triglycerides in the IDL particles are hydrolyzed by hepatic lipase leading to a further decrease in triglyceride content and the exchangeable apolipoproteins are transferred from the IDL particles to other lipoproteins leading to the formation of LDL.
The levels of LDL receptors in the liver are mainly regulated by the cholesterol content of the hepatocyte. 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. 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. 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.