Cholesterol is used as a carrier of polyunsaturated fatty acids. The good, bad and evil cholesterol Reverse cholesterol transport
82 Cholesterol can be synthesized in every eukaryotic cell, but primarily in the liver. Proceeds from acetyl-CoA, with the participation of ER enzymes and hyaloplasm. It consists of 3 stages: 1) formation of memalonic acid from acetyl CoA 2) synthesis of active isoprene from mimolonic acid with its condensation into squalene 3) conversion of squalene to cholesterol. HDL collects excess cholesterol from tissue, esterifies it, and transfers it to VLDL and chylomicrons (CMs). Cholesterol is a carrier of unsaturated fatty acids. LDL delivers cholesterol to tissues and all cells of the body have receptors for it. Cholesterol synthesis is regulated by the enzyme HMG reductase. All output is empty. enters the liver and is excreted with bile in the form of cholesterol or in the form of bile salts, but most of the bile is reabsorbed from the enterohepatic regulation. Cellular LDL receptors interact with the ligand, after which it is captured by the cell by endocytosis and disintegrates in lysosomes, while cholesterol esters are hydrolyzed. Free cholesterol inhibits HMG-CoA reductase, and denovo cholesterol synthesis promotes the formation of cholesteryl esters. As cholesterol concentration increases, the number of LDL receptors decreases. The concentration of cholesterol in the blood is highly dependent on hereditary and negative factors. An increase in the level of free and fatty acids in the blood plasma leads to increased secretion of VLDL by the liver and, accordingly, the entry of additional amounts of TAG and cholesterol into the bloodstream. Factors affecting free fatty acids: emotional stress, nicotine, coffee abuse, eating with long breaks and in large quantities.
No. 83 Cholesterol is a carrier of unsaturated fatty acids. LDL delivers cholesterol to tissues and all cells of the body have receptors for it. Cholesterol synthesis is regulated by the enzyme HMG reductase. All cholesterol that is excreted from the body enters the liver and is excreted with bile either in the form of cholesterol or in the form of bile salts, but most of the bile. reabsorbed from enterohepatic regulation. Bile which is synthesized in the liver from cholesterol.
The first synthesis reaction is image. 7-a-hydroxylase is inhibited by the end product of bile ducts. And the afterproduct of synthesis leads to the formation of 2 types of bile ducts. to-t: cholic and chenodeoxycholic. Conjugation is the addition of ionized glycine or taurine molecules to the carboxyl group of the bile. kt. Conjugation occurs in the liver cells and begins with the formation of an active form of bile. set – derivatives of CoA. then taurine or glycine is combined to form the result. 4 variants of conjugates: taurocholic or glycochenodeoxycholic, glycocholic. Gallstone disease is a pathological process in which stones are formed in the gallbladder, the basis of which is cholesterol. In most patients with cholelithiasis, the activity of HMG-CoA reductase is increased, therefore cholesterol synthesis is increased, and the activity of 7-alpha-hydroxylase is reduced. As a result, the synthesis of cholesterol is increased, and the synthesis of bile acids from it is slowed down. If these proportions are disturbed, then cholesterol begins to precipitate in the gallbladder. initially forming a viscous precipitate, cat. gradually becomes more solid.
Treatment of cholelithiasis. In the initial stage of stone formation, chenodeoxycholic acid can be used as a medicine. Getting into the gallbladder, this bile acid gradually dissolves the cholesterol sediment
Ticket 28
1.Features of microsomal oxidation, its biological role. Cytochrome P 450
Microsomal oxidation. In the membranes of smooth ER, as well as in the mitochondria of the membranes of some organs, there is an oxidative system that catalyzes the hydroxylation of a large number of different substrates. This oxidative system consists of 2 chains of oxidized NADP-dependent and NAD-dependent, NADP-dependent monooxidase chain consists of BC-NADP, flavoprotein with coenzyme FAD and cytochrome P450. The NADH dependent oxidation chain contains flavoprotein and cytochrome B5. both chains can exchange and when the endoplasmic reticulum is released from the CL membranes, it disintegrates into parts, each of which forms a closed vesicle-microsome. CR450, like all cytochromes, belongs to hemoproteins, and the protein part is represented by one polypeptide chain, M = 50 thousand. It is capable of forming a complex with CO2 - it has a maximum absorption at 450 nm. The oxidation of xenobiotics occurs at different rates, induction and inhibitors of microsomal oxidation systems are known. The rate of oxidation of certain substances may be limited by competition for the enzyme complex of microsomal fractions. Thus, the simultaneous administration of 2 competing drugs leads to the fact that the removal of one of them may be delayed and this will lead to its accumulation in the body. In this case, the drug can induce activation of the microsomal oxidase system - the elimination of simultaneously prescribed drug drugs is accelerated. Inducers of microsomes can Use as a medicine if necessary to activate the processes of neutralization of endogenous metabolites. In addition to the detoxification reactions of xenobiotics, the microsomal oxidation system can cause toxicity of initially inert substances.
Cytochrome P450 is a hemoprotein, contains a prosthetic group - heme, and has binding sites for O2 and substrate (xenobiotic). Molecular O2 in the triplet state is inert and is not able to interact with organ compounds. To make O2 reactive, it is necessary to convert it into a singlet, using enzyme systems for its reduction (monoxygenase system).
2. The fate of cholesterol in the body..
HDL collects excess cholesterol from tissue, esterifies it, and transfers it to VLDL and chylomicrons (CMs). Cholesterol is a carrier of unsaturated fatty acids. LDL delivers cholesterol to tissues and all cells of the body have receptors for it. Cholesterol synthesis is regulated by the enzyme HMG reductase. All cholesterol that is excreted from the body enters the liver and is excreted with bile either in the form of cholesterol or in the form of bile salts, but most of the bile. reabsorbed from enterohepatic regulation. Bile which is synthesized in the liver from cholesterol. In the body, 200-600 mg of bile are synthesized per day. kt. The first synthesis reaction is image. 7-a-hydroxylase is inhibited by the end product of bile ducts. And the afterproduct of synthesis leads to the formation of 2 types of bile ducts. to-t: cholic and chenodeoxycholic. Conjugation is the addition of ionized glycine or taurine molecules to the carboxyl group of the bile. kt. Conjugation occurs in the liver cells and begins with the formation of an active form of bile. set – derivatives of CoA. then taurine or glycine is combined to form the result. 4 variants of conjugates: taurocholic or glycochenodeoxycholic, glycocholic. Gallstone disease is a pathological process in which stones are formed in the gallbladder, the basis of which is cholesterol. In most patients with cholelithiasis, the activity of HMG-CoA reductase is increased, therefore cholesterol synthesis is increased, and the activity of 7-alpha-hydroxylase is reduced. As a result, the synthesis of cholesterol is increased, and the synthesis of bile acids from it is slowed down. If these proportions are disturbed, then cholesterol begins to precipitate in the gallbladder. initially forming a viscous precipitate, cat. gradually becomes more solid. Cholesterol stones are usually white in color, while mixed stones are brown in different shades. Treatment of cholelithiasis. In the initial stage of stone formation, chenodeoxycholic acid can be used as a medicine. Once in the gallbladder, this bile acid gradually dissolves the cholesterol sediment, but this is a slow process that requires several months. The structural basis of cholesterol cannot be broken down into CO2 and water, so the basic. quantity is excreted only in the form of bile. kt. A certain amount of bile. It is excreted unchanged, and some of it is exposed to bacterial enzymes in the intestines. Some of the cholesterol molecules in the intestine, under the influence of bacterial enzymes, are reduced at the double bond, forming two types of molecules - cholestanol, coprostanol, excreted in feces. From 1 to 1.3 g of cholesterol is removed from the body per day. the main part is removed with feces
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.
CHOLESTEROL SYNTHESIS
It occurs mainly in the liver on the membranes of the endoplasmic reticulum of hepatocytes. This cholesterol is endogenous. There is a constant transport of cholesterol from the liver to the tissues. Dietary (exogenous) cholesterol is also used to build membranes. The key enzyme in cholesterol biosynthesis is HMG reductase (beta-hydroxy, beta-methyl, glutaryl-CoA reductase). This enzyme is inhibited by negative feedback by the end product, cholesterol.
TRANSPORT OF CHOLESTEROL.
Dietary cholesterol is transported by chylomicrons and ends up in the liver. Therefore, the liver is a source of both dietary cholesterol (arrived there as part of chylomicrons) and endogenous cholesterol for tissues.
In the liver, VLDL - very low density lipoproteins (consist of 75% cholesterol), as well as LDL - low density lipoproteins (they contain the apoprotein apoB 100) are synthesized and then enter the blood.
Almost all cells have receptors for apoB 100. Therefore, LDL is fixed on the surface of cells. In this case, the transition of cholesterol into cell membranes is observed. Therefore, LDL is able to supply tissue cells with cholesterol.
In addition, cholesterol is released from tissues and transported to the liver. High-density lipoproteins (HDL) transport cholesterol from tissues to the liver. They contain very few lipids and a lot of protein. HDL synthesis occurs in the liver. HDL particles are disc-shaped and contain apoproteins apoA, apoC and apoE. In the bloodstream, an enzyme protein attaches to LDL lecithin cholesterol acyltransferase(LHAT) (see picture).
ApoC and apoE can move from HDL to chylomicrons or VLDL. Therefore, HDL are donors of apoE and apoC. ApoA is an activator of LCAT.
LCAT catalyzes the following reaction:
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This is a reaction where a fatty acid is transferred from the R2 position to cholesterol.
The reaction is very important because the resulting cholesterol ester is a very hydrophobic substance and immediately passes into the HDL core - this is how excess cholesterol is removed from the HDL cell membranes upon contact. HDL then goes to the liver, where it is destroyed, and excess cholesterol is removed from the body.
An imbalance between the amounts of LDL, VLDL and HDL can cause cholesterol retention in tissues. This leads to atherosclerosis. Therefore, LDL is called atherogenic lipoproteins, and HDL is called antiatherogenic lipoprotein. With hereditary HDL deficiency, early forms of atherosclerosis are 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)
