The good, bad and evil cholesterol. Cholesterol is used as a carrier of polyunsaturated fatty acids Transport of cholesterol and its esters in the body
Cholesterol is transported in the blood only as part of drugs. LPs ensure the entry of exogenous cholesterol into tissues, determine the flow of cholesterol between organs and remove excess cholesterol from the body.
Transport of exogenous cholesterol. Cholesterol comes from food in an amount of 300-500 mg/day, mainly in the form of esters. After hydrolysis, absorption in micelles, and esterification in the cells of the intestinal mucosa, cholesterol esters and a small amount of free cholesterol are included in the chemical composition and enter the blood. After fats are removed from cholesterol under the action of LP lipase, cholesterol in the residual cholesterol is delivered to the liver. Residual CMs interact with liver cell receptors and are captured by the mechanism of endocytosis. Lysosome enzymes then hydrolyze the components of residual cholesterol, resulting in the formation of free cholesterol. Exogenous cholesterol entering liver cells in this way can inhibit the synthesis of endogenous cholesterol, slowing down the rate of HMG-CoA reductase synthesis.
Transport of endogenous cholesterol as part of VLDL (pre-β-lipoproteins). The liver is the main site of cholesterol synthesis. Endogenous cholesterol, synthesized from the original substrate acetyl-CoA, and exogenous cholesterol, received as part of residual cholesterol, form a common pool of cholesterol in the liver. In hepatocytes, triacylglycerols and cholesterol are packaged into VLDL. They also include apoprotein B-100 and phoepholipids. VLDL are secreted into the blood, where they receive apoproteins E and C-II from HDL. In the blood, VLDL is acted upon by LP lipase, which, as in CM, is activated by apoC-II and hydrolyzes fats to glycerol and fatty acids. As the amount of TAG in VLDL decreases, they turn into DILI. When the amount of fat in HDL decreases, apoprotein C-II is transferred back to HDL. The content of cholesterol and its esters in LPPP reaches 45%; Some of these lipoproteins are taken up by liver cells through LDL receptors, which interact with both apoE and apoB-100.
Transport of cholesterol in LDL. LDL receptors. LP lipase continues to act on LDLP remaining in the blood, and they are converted into LDL, containing up to 55% cholesterol and its esters. Apoproteins E and C-II are transported back to HDL. Therefore, the main apoprotein in LDL is apoB-100. Apoprotein B-100 interacts with LDL receptors and thus determines the further pathway of cholesterol. LDL is the main transport form of cholesterol in which it is delivered to tissues. About 70% of cholesterol and its esters in the blood are contained in LDL. From the blood, LDL enters the liver (up to 75%) and other tissues that have LDL receptors on their surface. The LDL receptor is a complex protein consisting of 5 domains and containing a carbohydrate part. LDL receptors are synthesized in the ER and Golgi apparatus, and then exposed on the cell surface, in special recesses lined with the protein clathrin. These depressions are called bordered pits. The surface-protruding N-terminal domain of the receptor interacts with the proteins apoB-100 and apoE; therefore, it can bind not only LDL, but also LDLP, VLDL, and residual CM containing these apoproteins. Tissue cells contain a large number of LDL receptors on their surface: for example, on one fibroblast cell there are from 20,000 to 50,000 receptors. It follows from this that cholesterol enters cells from the blood mainly as part of LDL. If the amount of cholesterol entering a cell exceeds its need, then the synthesis of LDL receptors is suppressed, which reduces the flow of cholesterol from the blood into the cells. When the concentration of free cholesterol in the cell decreases, on the contrary, the synthesis of HMG-CoA reductase and LDL receptors is activated. Hormones participate in the regulation of the synthesis of LDL receptors: insulin and triiodothyronine (T 3), half-term hormones. They increase the formation of LDL receptors, and glucocorticoids (mainly cortisol) decrease. The effects of insulin and T3 may likely explain the mechanism of hypercholesterolemia and the increased risk of atherosclerosis in diabetes mellitus or hypothyroidism.
The role of HDL in cholesterol metabolism. HDL performs 2 main functions: they supply apoproteins to other lipids in the blood and participate in the so-called “reverse cholesterol transport”. HDL is synthesized in the liver and in small quantities in the small intestine in the form of “immature lipoproteins” - precursors to HDL. They are disc-shaped, small in size and contain a high percentage of proteins and phospholipids. In the liver, HDL includes apoproteins A, E, C-II, and the LCAT enzyme. In the blood, apoC-II and apoE are transferred from HDL to CM and VLDL. HDL precursors practically do not contain cholesterol and TAG and are enriched in cholesterol in the blood, receiving it from other lipoproteins and cell membranes. There is a complex mechanism for the transfer of cholesterol to HDL. On the surface of HDL there is the enzyme LCAT - lecithin cholesterol acyltransferase. This enzyme converts cholesterol, which has a hydroxyl group exposed on the surface of lipoproteins or cell membranes, into cholesterol esters. The fatty acid radical is transferred from phosphatidylcholitol (lecithin) to the hydroxyl group of cholesterol. The reaction is activated by apoprotein A-I, which is part of HDL. The hydrophobic molecule, cholesterol ester, moves into HDL. Thus, HDL particles are enriched in cholesterol esters. HDL increases in size, changing from small disk-shaped particles to spherical particles called HDL3, or “mature HDL.” HDL 3 partially exchanges cholesterol esters for triacylglycerols contained in VLDL, LDLP and CM. This transfer involves "cholesterol ester transfer protein"(also called apoD). Thus, part of the cholesterol esters is transferred to VLDL, LDLP, and HDL 3 due to the accumulation of triacylglycerols increases in size and turns into HDL 2. VLDL, under the action of LP lipase, is converted first into LDLP, and then into LDL. LDL and LDLP are taken up by cells through LDL receptors. Thus, cholesterol from all tissues returns to the liver mainly as LDL, but LDLP and HDL2 also participate in this. Almost all the cholesterol that must be excreted from the body enters the liver and is excreted from this organ in the form of derivatives with feces. The path of cholesterol returning to the liver is called “reverse transport” of cholesterol.
37. Conversion of cholesterol into bile acids, removal of cholesterol and bile acids from the body.
Bile acids are synthesized in the liver from cholesterol. Some bile acids in the liver undergo a conjugation reaction - combining with hydrophilic molecules (glycine and taurine). Bile acids ensure the emulsification of fats, the absorption of the products of their digestion and some hydrophobic substances supplied with food, such as fat-soluble vitamins and cholesterol. Bile acids are also absorbed, return through the juridical vein to the liver and are repeatedly used to emulsify fats. This pathway is called the enterohepatic circulation of bile acids.
Bile acid synthesis. The body synthesizes 200-600 mg of bile acids per day. The first synthesis reaction, the formation of 7-α-hydroxycholesterol, is regulatory. The enzyme 7-α-hydroxylase, which catalyzes this reaction, is inhibited by the end product, bile acids. 7-α-Hydroxylase is a form of cytochrome P 450 and uses oxygen as one of its substrates. One oxygen atom from O 2 is included in the hydroxyl group at position 7, and the other is reduced to water. Subsequent synthesis reactions lead to the formation of 2 types of bile acids: cholic and chenodeoxycholic, which are called “primary bile acids.”
Removing cholesterol from the body. The structural basis of cholesterol - rings - cannot be broken down into CO 2 and water, like other organic components that come from food or are synthesized in the body. Therefore, the main amount of cholesterol is excreted in the form of bile acids.
Some bile acids are excreted unchanged, and some are exposed to bacterial enzymes in the intestines. The products of their destruction (mainly secondary bile acids) are excreted from the body.
Some cholesterol molecules in the intestine, under the action of bacterial enzymes, are reduced at the double bond in ring B, resulting in the formation of 2 types of molecules - cholestanol and coprostanol, excreted in feces. From 1.0 g to 1.3 g of cholesterol is excreted from the body per day, the main part is removed with feces,
Related information.
Transport of cholesterol and its esters is carried out low and high density lipoproteins.
High density lipoproteins
General characteristics
- are formed in liverde novo, V plasma blood during the breakdown of chylomicrons, a certain amount in the wall intestines,
- approximately half of the particle consists of proteins, another quarter is phospholipids, the rest is cholesterol and TAG (50% protein, 25% PL, 7% TAG, 13% cholesterol esters, 5% free cholesterol),
- the main apoprotein is apo A1, contain apoE And apoCII.
Function
- Transport of free cholesterol from tissues to the liver.
- HDL phospholipids are a source of polyenoic acids for the synthesis of cellular phospholipids and eicosanoids.
Metabolism
1. HDL synthesized in the liver ( nascent or primary) contains mainly phospholipids and apoproteins. The remaining lipid components accumulate in it as they are metabolized in the blood plasma.
2-3. In blood plasma, nascent HDL first turns into HDL 3 (conventionally, it can be called “mature”). The main thing in this transformation is that HDL
- takes away from cell membranes free cholesterol through direct contact or with the participation of specific transport proteins,
- interacting with cell membranes, gives them part phospholipids from its shell, thus delivering polyene fatty acids into cells
- interacts closely with LDL and VLDL, receiving from them free cholesterol. In exchange, HDL 3 releases cholesterol esters formed due to the transfer of fatty acids from phosphatidylcholine (PC) to cholesterol ( LCAT reaction, see point 4).
4. A reaction actively occurs inside HDL with the participation of lecithin:cholesterol acyltransferase(LCAT reaction). In this reaction, a polyunsaturated fatty acid residue is transferred from phosphatidylcholine(from the shell of HDL itself) to the resulting free cholesterol with the formation of lysophosphatidylcholine (lysoPC) and cholesterol esters. LysoPC remains inside HDL, cholesterol ester is sent to LDL.
Cholesterol esterification reaction
with the participation of lecithin: cholesterol acyltransferase
5. As a result, primary HDL is gradually converted, through the mature form of HDL 3, into HDL 2 (residual, remnant). At the same time, additional events occur:
- interacting with different forms of VLDL and CM, HDL obtain acyl-glycerols (MAG, DAG, TAG), and exchange cholesterol and its esters,
- HDL they donate apoE and apoCII proteins to the primary forms of VLDL and CM, and then take back apoCII proteins from the residual forms.
Thus, during the metabolism of HDL, there is an accumulation of free cholesterol, MAG, DAG, TAG, lysoPC and loss of the phospholipid membrane. Functional abilities of HDLs are decreasing.
Transport of cholesterol and its esters in the body
(numbers correspond to HDL metabolism points in the text)
Low density lipoproteins
General characteristics
- are formed in hepatocytes de novo and in the vascular system of the liver under the influence of hepatic TAG lipase from VLDL,
- the composition is dominated by cholesterol and its esters, the other half of the mass is divided by proteins and phospholipids (38% cholesterol esters, 8% free cholesterol, 25% proteins, 22% phospholipids, 7% triacylglycerols),
- the main apoprotein is apoB-100,
- normal blood level is 3.2-4.5 g/l,
- the most atherogenic.
Function
1. Transport of cholesterol into cells that use it
- for reactions of sex hormone synthesis ( gonads), glucocorticoids and mineralocorticoids ( adrenal cortex),
- for conversion to cholecalciferol ( leather),
- for the formation of bile acids ( liver),
- for excretion as part of bile ( liver).
2. Transport of polyene fatty acids in the form of cholesterol esters into some loose connective tissue cells(fibroblasts, platelets, endothelium, smooth muscle cells), into the epithelium of the glomerular membrane kidney, into cells bone marrow, into corneal cells eye, V neurocytes, V adenohypophysis basophils.
Cells of loose connective tissue actively synthesize eicosanoids. Therefore, they need a constant supply of polyunsaturated fatty acids (PUFAs), which is carried out through the apo-B-100 receptor, i.e. adjustable absorption LDL, which carry PUFAs as part of cholesterol esters.
A feature of cells that absorb LDL is the presence of lysosomal acid hydrolases that break down cholesterol esters. Other cells do not have such enzymes.
An illustration of the importance of PUFA transport into these cells is the inhibition by salicylates of the enzyme cyclooxygenase, which forms eicosanoids from PUFAs. Salicylates have been successfully used in cardiology to suppress the synthesis of thromboxanes and reduce thrombus formation, with fever, as an antipyretic by relaxing the smooth muscles of skin vessels and increasing heat transfer. However, one of the side effects of the same salicylates is the suppression of prostaglandin synthesis in kidneys and decreased renal circulation.
Also, PUFAs can pass into the membranes of all cells, as mentioned above (see “Metabolism of HDL”) as part of phospholipids from the HDL shell.
Metabolism
1. In the blood, primary LDL interacts with HDL, releasing free cholesterol and receiving esterified cholesterol. As a result, cholesterol esters accumulate in them, the hydrophobic core increases, and the protein “pushes out” apoB-100 to the surface of the particle. Thus, primary LDL becomes mature.
2. All cells that use LDL have a high-affinity receptor specific for LDL - apoB-100 receptor. About 50% of LDL interacts with apoB-100 receptors in various tissues and approximately the same amount is absorbed by hepatocytes.
3. When LDL interacts with the receptor, endocytosis of the lipoprotein and its lysosomal breakdown into its constituent parts occurs - phospholipids, proteins (and further to amino acids), glycerol, fatty acids, cholesterol and its esters.
- HS turns into hormones or included in membranes,
- excess membrane cholesterol are deleted with the help of HDL,
- PUFAs brought with cholesterol esters are used for synthesis eicosanoids or phospholipids.
- if it is impossible to remove the CS part of it esterified with oleic or linoleic acid enzyme acyl-SCoA:cholesterol acyltransferase(AHAT reaction),
Synthesis of cholesterol oleate with the participation
acyl-SKoA-cholesterol acyltransferases
Per quantity apoB-100-receptors are influenced by hormones:
- insulin, thyroid and sex hormones stimulate the synthesis of these receptors,
- glucocorticoids reduce their number.
Four types of lipoproteins circulate in the blood, differing in their content of cholesterol, triglycerides and apoproteins. They have different relative densities and sizes. Depending on the density and size, the following types of lipoproteins are distinguished:
Chylomicrons are fat-rich particles that enter the blood from the lymph and transport dietary triglycerides.
They contain about 2% apoprotein, about 5% XO, about 3% phospholipids and 90% triglycerides. Chylomicrons are the largest lipoprotein particles.
Chylomicrons are synthesized in the epithelial cells of the small intestine, and their main function is to transport triglycerides received from food. Triglycerides are delivered to adipose tissue, where they are deposited, and to muscles, where they are used as a source of energy.
The blood plasma of healthy people who have not eaten for 12-14 hours does not contain chylomicrons or contains an insignificant amount.
Low-density lipoproteins (LDL) - contain about 25% apoprotein, about 55% cholesterol, about 10% phospholipids and 8-10% triglycerides. LDL is VLDL after it delivers triglycerides to fat and muscle cells. They are the main carriers of cholesterol synthesized in the body to all tissues (Fig. 5-7). The main protein of LDL is apoprotein B (apoB). Since LDL delivers cholesterol synthesized in the liver to tissues and organs and thereby contributes to the development of atherosclerosis, they are called atherogenic lipoproteins.
eat cholesterol (Fig. 5-8). The main protein of LPVHT is apoprotein A (apoA). The main function of HDL is to bind and transport excess cholesterol from all non-liver cells back to the liver for further excretion in bile. Due to the ability to bind and remove cholesterol, HDL is called antiatherogenic (prevents the development of atherosclerosis).
Low-density lipoproteins (LDL)
Phospholipid ■ Cholesterol
Triglyceride
Nezsterifi-
quoted
cholesterol
Apoprotein B
Rice. 5-7. Structure of LDL
Apoprotein A
Rice. 5-8. Structure of HDL
The atherogenicity of cholesterol is primarily determined by its belonging to one or another class of lipoproteins. In this regard, special attention should be paid to LDL, which is the most atherogenic for the following reasons.
LDL transports about 70% of total plasma cholesterol and is the particle richest in cholesterol, the content of which can reach up to 45-50%. The particle size (diameter 21-25 nm) allows LDL, along with LDL, to penetrate the vessel wall through the endothelial barrier, but, unlike HDL, which is easily removed from the wall, helping to remove excess cholesterol, LDL is retained in it because it has a selective affinity for its structural components. The latter is explained, on the one hand, by the presence of apoB in LDL, and on the other, by the existence of receptors for this apoprotein on the surface of the cells of the vessel wall. For these reasons, DILI are the main transport form of cholesterol for low-grade cells of the vascular wall, and under pathological conditions - a source of its accumulation in the vascular wall. That is why, with hyperlipoproteinemia, characterized by high levels of LDL cholesterol, relatively early and pronounced atherosclerosis and coronary artery disease are often observed.
Question 35. Regulation of cholesterol biosynthesis, cholesterol transport in the blood.
Key regulatory enzyme - HMG-CoA reductase, whose activity in the liver is regulated in three ways:
At the level of transcription of the HMG-CoA reductase gene. Corepressors of the process that reduce the rate of enzyme synthesis are cholesterol, bile acids and corticosteroid hormones, and inducers are insulin and thyroid hormones - T3 and T4;
Through phosphorylation and dephosphorylation, which is also regulated by hormones. Dephosphorylation is stimulated by insulin, which, due to the activation of protein phosphatase, converts the enzyme into a dephosphorylated active form, and glucagon, through the adenylate cyclase system, provides the mechanism for its phosphorylation and inactivation;
Reducing the amount of enzyme due to proteolysis of molecules, which is stimulated by cholesterol and bile acids. Part of the newly synthesized cholesterol is esterified to form esters. This reaction, as in enterocytes, is catalyzed by ACHAT, adding linoleic or oleic acid residues to cholesterol.
All lipoproteins participate in the transport of cholesterol and its esters through the blood.. Thus, chylomicrons transport cholesterol from the intestine through the blood to the liver as part of the XMost. In the liver, cholesterol, along with endogenous fats and phospholipids, is packaged into VLDL and secreted into the blood. In the bloodstream, immature VLDL receives membrane proteins ApoC II and ApoE from HDL and becomes mature, i.e. capable of interacting with lipid lipase, which hydrolyzes TAG in VLDL to IVF and glycerol. Particles, losing fat, decrease in size, but increase in density and turn first into DILI, and then into LDL.
36. The role of LDL and HDL in cholesterol transport.
Cholesterol in the blood is found in the following forms:
Total cholesterol
Low-density lipoprotein (LDL) cholesterol
High-density lipoprotein (HDL) cholesterol
LDL cholesterol is the main transport form of total cholesterol. It transports total cholesterol to tissues and organs. LP lipase continues to act on LDLP remaining in the blood, and they are converted into LDL, containing up to 55% cholesterol and its esters. Apoproteins E and C-II are transported back to HDL. Therefore, the main apoprotein in LDL is apoB-100. Apoprotein B-100 interacts with LDL receptors and thus determines the further pathway of cholesterol. LDL is the main transport form of cholesterol in which it is delivered to tissues. About 70% of cholesterol and its esters in the blood are contained in LDL. From the blood, LDL enters the liver (up to 75%) and other tissues that have LDL receptors on their surface. Determination of LDL cholesterol is carried out in order to detect an increase in cholesterol in the blood. With the development of vascular diseases, it is LDL cholesterol that is the source of cholesterol accumulation in the walls of blood vessels. The risk of developing atherosclerosis and coronary heart disease is more closely related to LDL cholesterol than to total cholesterol.
HDL cholesterol transports fats and cholesterol from one group of cells to another. Thus, HDL cholesterol transports cholesterol from the vessels of the heart, heart muscle, arteries of the brain and other peripheral organs to the liver, where bile is formed from cholesterol. HDL cholesterol removes excess cholesterol from the body's cells. HDL performs 2 main functions: they supply apoproteins to other lipids in the blood and participate in the so-called “reverse cholesterol transport”. HDL is synthesized in the liver and in small quantities in the small intestine in the form of “immature lipoproteins” - precursors to HDL. They are disc-shaped, small in size and contain a high percentage of proteins and phospholipids. In the liver, HDL includes apoproteins A, E, C-II, and the LCAT enzyme. In the blood, apoC-II and apoE are transferred from HDL to CM and VLDL. HDL precursors practically do not contain cholesterol and TAG and are enriched in cholesterol in the blood, receiving it from other lipoproteins and cell membranes.
(the question doesn’t say anything about fur-we, so I think that’s enough)
