lipid transport. Complex lipids and steroids
Transport forms of lipids
Transport and metabolic transformations of blood lipids
Newly synthesized TAGs, phospholipids and other absorbed lipids leave the cells of the intestinal mucosa, entering first into the lymph, and with the lymph flow into the blood. Due to the fact that most lipids are insoluble in the aquatic environment, their transport in the lymph, and then in the blood plasma, is carried out in combination with proteins.
Fatty acids in the blood are associated with albumin, and other lipids are transported as part of special particles - lipoproteins .
Electron microscopy of the selected types of lipoprotein particles showed that they are spherical particles, the diameter of which decreases with increasing density (table 1). Lipoproteins consist of a core that includes hydrophobic lipids - triacylglycerides, cholesterol esters, etc., while the outer part, in contact with blood plasma contains amphiphile lipids: phospholipids, free cholesterol. Protein Components (apoproteins) with their hydrophobic areas located in the inner part of lipoprotein particles, and hydrophilic - mainly on the surface.
Table 1. Characteristics of lipoproteins.
| Properties | VLDL | LPPP | LDL | HDL |
|
| Density g/l | < 0,95 | ||||
| Diameter, nm | |||||
| Electro-phoretic mobility | Stay at the start | Floating β | |||
| Place of education | Small intestine | VLDL catabolism | Catabolism of VLDL via LPPP | Liver, small intestine, catabolism of HM and VLDL |
|
| main function | Transport of exogenous TG | Transport of endogenous TG | LDL precursor | Cholesterol transport | reverse cholesterol transport |
| Compound: |
|||||
| Cholesterol | |||||
| Phospholipids | |||||
| Apoproteins | A, B-48, C, E | B-100, S, E | B-100, E | A, C, E |
|
Lipoprotein particles - macromolecular complexes, the inner part of which contains neutral lipids (TAGs and cholesterol esters), and the surface layer consists of phospholipids and specific lipid transport proteins called apolipoproteins.
Lipoproteins are classified on the basis of their mobility in an electric field (during electrophoresis). During electrophoresis, lipoproteins are divided into fractions, one of which remains at the start (chylomicrons), others migrate to the globulin zones - β-LP, pre-β-LP, α-LP.
According to the size of the hydration shell, they are usually divided into 5 classes: chylomicrons, VLDL, LPP, LDL, HDL.
According to the electrophoretic mobility, VLDL correspond to pre-β-LP, LDL - β-LP, HDL - α-LP, and HM remain at the start.
Apoproteins are lipoprotein envelope proteins non-covalently associated with phospholipids and cholesterol. Apoproteins maintain the structural integrity of lipoproteins, participate in the exchange processes between lipoproteins and are responsible for the interaction of lipoproteins with their receptors.
ApoLP promote the formation of LP micelles in the endoplasmic reticulum of hepatocytes, serve as ligands for specific receptors on the surface of the plasma membrane of cells and cofactors (activators and inhibitors) of the process of lipolysis and LP metabolism in the vascular bed.
The resulting chylomicrons are first secreted into the lymphatic capillaries. Then through the lymphatic system vessels with a current of lymph, they enter the blood. in the plaza in blood, the apoprotein composition of chylomicrons changes due to exchange with other types of lipoprotein particles (whether high density proteins - HDL) . In particular, on chi lomicrons receive apoprotein C, which is later required to activate their lipolysis.
The transformation of chylomicrons in blood plasma is determined mainly by the action of the enzyme - lipoprotein lipase (LPL) . This enzyme belongs to the lipase family. It is synthesized in the cells of muscle and adipose tissue, but functions on the outer surface of endothelial cells, you lining the walls of vessels from the inside. LPL catalyzes the reactionhydrolysis of triacylglycerides in the composition of chylomicrons with a flake reduction of fatty acid radicals in positions 1 and 3, as well as in position 1 in phospholipids. The 2-monoacylglycerides formed in the case of triacylglyceride cleavage subsequently spontaneously isomerize, turning into 1- or 3-monoacylglycerides, and undergo further cleavage with the participation of the same LPL to glycerol and fatty acid. This happens until the amount of triacylglycerides in the composition of lipoprotein particles decreases to 20% of the original content.
Fatty acids released during digestion lots are associated with blood plasma albumin and in such a plexus are transported to the cells of organs and tissues. Cells absorb fatty acids and use them as energy fossil fuel or building material(synthesis of own lipids in cells). The main consumers of fatty acids are adipose and muscle tissue.
As a result of the action of LPL, chylomicrons are destroyed, and fragments of these particles enter the liver, where they undergo final destruction. In the liver, both the protein component of chylomicrons (to amino acids) and unsplit or partially split triacylglycerides and other lipids are cleaved. Hepatic lipase and other enzymes are involved in this process.
Simultaneously, the liver intensively proceedslipid synthesis from the original substrates (acetic acid, glycerol, fatty acids, etc.). The transport of newly synthesized lipids from the liver to the blood, and from there to organs and tissues, is carried out by two other types of lipoproteins. birds that form in the liver - lipoproteins are very low density (VLDL) and high density lipoproteins (HDL) . The principles of arrangement of these particles are similar to those of chylomicrons. The difference is that VLDL and even more HDL are smaller than chylomicrons. The proportion of the protein component in their composition is higher (10.4 and 48.8% by weight of the particle, respectively), and the content of triacylglycerides is lower (31.4 and 1.8% by weight, respectively). As a result, the density of VLDL and HDL is higher than that of chylomicrons.
The main lipid component VLDL are triacylglycerides. However, unlike chylomicrons, these triacylglycerides are synthesized in liver cells. Therefore, they are called endogenous, while in the composition of chylomicrons they are called exogenous (ingested with food). VLDL sec are transported from the liver into the blood. There lipids found in their composition, just as it was in the case of chylomicrons, undergo LPL cleavage. Released fatty acids enter the cells of organs and tissues.
It should be noted that the level of LPL in muscle and adipose tissue fluctuates in such a way as to ensure the maximum supply of fatty acids to adipose tissue cells for their deposition after meals, and in the period between meals to muscle tissue cells to maintain their functions. At the same time, in adipose tissue, the main factor that increases the synthesis of catalytically active LPL, is insulin. Therefore, hyperinsulinemia which contributes to the period of absorption of food digestion products, will be accompanied by an increased intake of triacylglyceride cleavage products from chylomicrons and VLDL into adipose tissue for storage.
The main pathway for the formation of LDL- VLDLP lipolysis with LPL. It occurs directly in the bloodstream. During this reaction, a number of intermediates are formed. ducts or particles containing various amounts of tria cilglycerides. They have been collectively named lipoprotein Intermediate Density Ines (LPP) . Further fate LPPP can be folded in two ways: they either enter the liver from the bloodstream, or undergo further transformations (their mechanism is not well understood), transforming into LDL.
Major lipid component of the nucleus LDL are cholesterol esters. LDL is the main means of delivering cholesterol to the cells of organs and tissues (figure). First, the LDL particle interacts with one of the 15,000 receptors specific for these lipoproteins on the cell surface. At the next stage, the LDL particle associated with the receptor undergoes absorption by the cell. Within the formed endosomes, lipoproteins are cleaved from receptors.
Subsequently, LDL enters the lysosomes, where it breaks downstagger. Occurs in lysosomeshydrolysis of ef and rovcholesterol, included in the LDL . As a result free cholesterol or its oxidized forms are formed. Free cholesterol is used for various purposes: lives as a structural component of cell membranes, a substrate for the synthesis of steroid hormones and bile acids. Pro the ducts of its oxidative transformation have a regulatory torsion effect on the body.
Control mechanisms coordinate the use intra- and extracellular sources of cholesterol. When sufficient exact amount of LDL, mammalian cells preferentially use LDL as a source of cholesterol through receptors. At this time, the intracellular system of cholesterol synthesis is, as it were, in reserve, does not function at full strength.
An important role in the targeted delivery of lipoproteins to The pathway of their metabolism belongs to apoproteins. They blow the interaction of lipoproteins with enzymes and cell surface receptors.
Reverse transport of cholesterol from peripheral tissues to the liver via HDL. These lipoprotein particles remove excess free rified) cholesterol from the cell surface.
HDL - this is a whole class of lipoprotein particles, which rye significantly differ from each other in lipid and apoprotein composition, size and function. Are formed HDL in the liver. From there they are secreted into the bloodstream in "not mature" form, i.e., they have a disc-shaped form. This form is due to the absence of a core of neutral lipids in them. dov. Phosphos are their main lipid component. pids.
Transfer of free cholesterol from cells to HDL due to the difference in its concentrations on the surface of cell membranes and lipoprotein particles. Therefore, it continues until the concentration of cholesterol between the donor (membrane surface) and the acceptor (HDL) is equalized. Maintenance of the concentration gradient is ensured by the constant conversion of free cholesterol to HDL , into cholesterol esters. This reac cation is catalyzed by an enzyme lecithin-cholesterolacnltrans ferase (LHAT) . The resulting cholesterol esters are completely hydrophobic compounds. (unlike free cholesterol, which has a hydroxyl group that makes it hydrophilic). By virtue of Because of their hydrophobicity, cholesterol esters lose their ability to diffuse and cannot return back to the cell. They form a hydrophobic core inside the particles, due to which HDL acquire a spherical shape. In this form, HDL with the blood flow enters the liver, where they are destroyed.
The released cholesterol esters serve as the initial substrate for the formation of bile acids.
Lipoproteins play a key role in lipid transport and metabolism. .
Lipoproteins- spherical structures that are formed due to the combination of cholesterol, cholesterol esters and triglycerides of fatty acids. They form a core surrounded by a shell 2 nm thick. The composition of the shell includes phospholipid molecules, non-esterified cholesterol, and specific proteins - apoproteins, which are always on the surface of lipoproteins. Now there are 5 classes of apoproteins - A, B, C, D, E.
Functions of apoproteins:
Contribute to the dissolution of ECS and TG
Regulate the reactions of lipids with enzymes
Bind lipoproteins to cell receptors
Determine the functional properties of the drug.
All lipoproteins are divided into four classes, which differ in the composition of the nucleus, the type of apoproteins and functions. The higher the protein content in the LP and the lower the content of triglycerides, the smaller the particle size of the LP and the higher their density.
Formed in the wall of the small intestine chylomicrons- large spherical particles, 90 % made up of triglycerides. The function of chylomicrons is the transport of dietary cholesterol and fatty acids from the intestines to peripheral tissues (skeletal muscles, myocardium, adipose tissue, where they are used as an energy substrate) and the liver. The protein shell of chylomicrons includes apoprotein B-48. Apoprotein B-48 is synthesized only in intestinal cells. In its absence, chylomicrons are not formed. Chylomicrons enter the blood through the intestinal lymphatic system through the thoracic lymphatic duct. In the blood, chylomicrons interact with HDL and acquire from them apo C-II and apo E, forming mature forms. Protein apo C-II is an activator of the enzyme lipoprotein lipase, the apoE protein is required to remove residual chylomicrons from the blood.
VLDL (very low density lipoproteins). Composed of 60% fat and 18% phospholipids. Proteins and cholesterol are approximately equal.
Metabolism of VLDL
1. Primary VLDL are formed in the liver from dietary fats supplied with chylomicrons and newly synthesized fats from glucose. Contain only apoB-100;
2. In the blood, primary VLDL interact with HDL and acquire apoC-II and apoE from them, forming mature forms.
3. On the capillary endothelium, mature VLDL are exposed to lipoprotein lipase with the formation of free fatty acids. Fatty acids move into the cells of the organ, or remain in the blood plasma and, in combination with albumin, are carried with the blood to other tissues.
4. Residual VLDL (also called Intermediate Density Lipoprotein, LDLP)
LDL (low density lipoprotein) are the most atherogenic
are the main transport form of cholesterol. They contain about 6% TG, the maximum amount of cholesterol (50%) and 22% protein.
The LDL particle contains as a protein component one molecule of apolipoprotein B-100 (apoB-100), which stabilizes the structure of the particle and is a ligand for the LDL receptor. LDL sizes vary from 18 to 26 nm. .
LDL is formed from VLDL during the hydrolysis of the latter by lipoprotein lipase and hepatic lipase. At the same time, the relative content of triglycerides in the particle decreases markedly, while cholesterol increases. Thus, LDL is the final step in the exchange of endogenous (synthesized in the liver) lipids in the body. They carry cholesterol in the body, as well as triglycerides, carotenoids, vitamin E and some other lipophilic components.
The level of LDL cholesterol correlates with a high risk of developing atherosclerosis and its manifestations such as myocardial infarction, stroke and HDL. It should be noted that small LDL are more atherogenic than larger ones.
The hereditary form of the disease with high LDL levels is hereditary hypercholesterolemia or type II hyperlipoproteinemia.
Cellular uptake of LDL
If the cell needs cholesterol, it synthesizes LDL receptors, which, after synthesis, are transported to the cell membrane. LDL circulating in the blood binds to these transmembrane receptors and is endocytosed by the cell. After absorption, LDL is delivered to endosomes, and then to lysosomes, where cholesterol esters are hydrolyzed, and cholesterol enters the cell.
HDL (high density lipoproteins) - produced in liver cells. These are the smallest lipoproteins. – 7-14nm. They consist of proteins (50%), 75% are apoprotein A.; 30% are phospholipids.
After leaving the hepatocyte, they are disc-shaped, but, circulating in the blood and absorbing cholesterol, they turn into spherical structures. The function of HDL is to remove excess cholesterol from the cells of peripheral tissues. This is facilitated by the liver enzyme - lecithin-cholesterol-acyltransferase, which is located on the surface of HDL, due to interaction with apaprotein A .. This enzyme ensures the transformation of cholesterol into its esters and translation into the nucleus. This is what allows HDL to remove excess cholesterol. Further, HDL enters the liver and excess cholesterol is excreted in the bile.
In the blood, lipoproteins and chylomicrons are found with two lipases, lipoprotein lipase and baked triacylglycerol lipase.
Lipoprotein lipase is located on the surface of the endothelium of the capillaries of muscle and adipose tissue. This lipase has an affinity for apoprotein-C and therefore binds to VLDL and chylomicrons. In the nucleus, fats are broken down to fatty acids, which enter the cells of adipose tissue, triglycerides are converted there and accumulate in reserve, and into muscle cells, where they are used as an energy substrate. Remaining chylomicrons lose apoprotein C and bind to HDL.
Hepatic triglyceride lipase also breaks down fats in chylomicrons and VLDL, but its cleavage products are utilized by myocardial cells and skeletal muscles. Chylomicrons are converted to chylomicron remnants and VLDL to LDL.
The maintenance of cholesterol metabolism occurs automatically with the participation of specific lipoprotein receptors located on the membrane of hepatocytes. Synthesis of cholesterol in hepatocytes is determined by the total number and load of receptors for LDL and HDL. With a low level of cholesterol and a small number of receptors, cholesterol synthesis is activated in hepatocytes. The interaction of the cholesterol-LDL molecular complex with normal expression of the LDL receptor on the cell surface leads to pinocytosis of the molecular complex. After pinocytosis, the complex is incorporated into lysosomes, where free cholesterol is released. An increase in the concentration of free cholesterol in the cell reduces the activity of the key enzyme of intracellular cholesterol synthesis, hydroxymethylglutaryl-coenzyme A-reductase. With age, there is a restriction of this receptor mechanism, and the increased intake of cholesterol is not accompanied by a restriction of its synthesis in the liver. Moreover, under atherogenic conditions, hepatocytes switch to new type excretion of cholesterol: in hepatocytes, the synthesis of apoprotein B is activated and the formation and release of VLDL is enhanced.
Thus, the main part of atherogenic lipoproteins is formed, metabolized and excreted from the body by the liver, therefore, disturbances in the regulation of the exchange of these particles in the liver are responsible for the development of atherosclerosis.
The basis of atherosclerosis violation of cholesterol metabolism and the predominance of atherogenic lipoproteins (LDL, VLDL ). It has now been proven that the starting line of atherosclerosis is the oxidative modification of lipoproteins associated with a prolonged imbalance in the body between pro- and antioxidants. Especially susceptible to oxidative modification of LDL, as they contain a lot of linoleic acid.
It turned out that lipoproteins have their own protection against oxidative stress in the form of molecules of ά-TF, β-carotene and others, the total content of which reaches 14 nM/mg of protein in lipoprotein. But even in normal LDL, a high content of hydroperoxides was found. The ability to oxidize LDL increases when they enter the intima of the vessels.
In addition, endothelial damage is an important factor in atherosclerotic vascular disease. Damage to the endothelium promotes the entry of LDL into the vascular wall . The endothelium is normally damaged most significantly in the main vessels under increased mechanical stress. LDL are sent to damaged areas, delivering an energy substrate for recovery, but in these areas they come into contact with free metals of variable valence, resulting in their oxidative modification. Oxidized LDL becomes toxic to the endothelium. In addition to hyperlipidemia, other factors also affect the endothelium: arterial hypertension, hormonal dysfunction, changes in blood rheology, smoking, and diabetes.
Mechanism of atherogenesis
1. Under the influence of modified LDL, the endothelium is damaged and the surface properties of monocytes and platelets change, which increases their adhesiveness.
2. Oxidized LDL exhibit chemoattractant properties.
3. After fixation on the endothelium, the monocyte migrates between endothelial cells to the subendothelial layer and turns into a macrophage, which, with the participation of special “cleaner” receptors, begins to capture lipids. Lipid uptake is also carried out by non-receptor pathways. This causes the formation of foam cells.
4. Macrophages produce damaging substances (leukotrienes, interleukins), which in turn adversely affect adjacent endothelial cells.
5. Activated macrophages produce several growth factors that have a mitogenic effect on smooth muscle cells and cause their migration to the intima, and stimulate the migration of fibroblasts, as well as the formation of connective tissue.
6. When the endothelium is damaged, platelets also have a pathogenic effect, which, when in contact with the endothelium, cause cell retraction. After that, platelets begin to interact with foam cells and connective tissue cells. It is also possible that platelets aggregate and form a parietal thrombus. Growth factors released during platelet activation cause proliferation of smooth muscle cells. The proliferating cells in turn produce a growth factor leading to the progression of the lesion.
7. Retraction of endothelial cells may occur due to the accumulation of cholesterol, low density lipoproteins in them. Excessive content of them violates the compliance of cells. Therefore, in places that are most exposed to blood flow (bifurcation areas, vessel discharge), separation of endothelial cells occurs due to rigidity. Altered endothelial cells also begin to produce growth factors, under the influence of which strips and plaques are formed.
The cellular composition of the plaques turned out to be similar to the composition of chronic inflammation occurring in the intima of the arteries. Currently, atherosclerotic lesions are considered as a polyetiological reaction of the vascular wall similar to inflammation, which appears in early childhood.
Mass epidemiological surveys of the population various countries made it possible to identify a number of factors affecting the frequency of atherosclerosis - risk factors. The importance of age, sex and family predisposition is not questioned. Among other factors, the main ones are: hyperlipidemia, arterial hypertension, smoking, diabetes. There is a relationship between the severity of atherosclerosis and exposure to various stressors, depression, physical inactivity, obesity, hyperuricemia, consumption of strong coffee and tea.
Of decisive importance for the onset and progression of atherosclerosis is the ratio of LP of various classes: LDL, VLDL have an atherogenic, and HDL - anti-atherogenic effect. The highest risk of developing atherosclerosis is observed in individuals with a high content of LDL and VLDL and low - HDL.
Cholesterol norms
Total cholesterol levels in blood - 3.0-6.0 mmol/l.
Norms content LDL cholesterol: for men- 2.25-4.82 mmol / l, for women- 1.92-4.51 mmol / l.
Norms level HDL cholesterol: for men- 0.7-1.73 mmol/l, for women- 0.86-2.28 mmol/l
Mechanism of atherogenesis
(formation of atherosclerotic plaque)
Situational tasks for independent work students
Task 1
A biochemical study of blood in patient X. showed that the value of the cholesterol atherogenic coefficient is 5 (norm ≤3). According to the patient, some time ago he underwent treatment at the endocrinology clinic for moderately severe hypothyroidism.
Test questions:
1. Is the patient at high risk of developing atherosclerosis?
2. What is the mechanism of the relationship between hypercholesterolemia and hypothyroidism? Justify the answer.
Task 2
A 22-year-old man was admitted to the clinic with complaints of pain in the region of the heart. The patient reported that he was diagnosed with angina pectoris 2 years ago. Examination revealed atherosclerotic plaques in subepicardial coronary arteries and large cerebral vessels. The content of cholesterol in the blood, LDL and LPPP in the blood plasma exceeds the upper limit of the norm by several times. The patient underwent a liver biopsy, which revealed a decrease in the number of receptors for LDL and LDL.
Test questions:
1. Does heredity matter in the occurrence and development of the detected pathology?
2. Is there a link between a decrease in the number of LDL receptors and hypercholesteremia?
3. What are the preventive measures for this pathology?
Task 3
Patient K., aged 58, suffers from arterial hypertension. In the last 1.5 years, she began to notice an increase in body weight, chilliness in her legs, numbness and pain in the calf muscles when walking, and then at rest (mainly at night, as a result of which her sleep was disturbed). 5 months ago, an erosion appeared in the lower third of the right shin, and then an ulcer, painless and not amenable to treatment. There is a constant elevated (up to 37.2-37.4 ° C) body temperature. At the doctor's appointment, the patient presented, in addition to the above, also complaints of dry mouth, thirst, increased fluid intake (4-5 liters per day), frequent profuse urination. Objectively: the skin on the legs is dry, pale, cold to the touch. Palpation does not determine the pulsation of the arteries in the popliteal fossa and on the foot. Blood test elevated levels of cholesterol, fibrinogen, platelets, GPC 180 mg%
Test questions:
1. What forms of pathology, in addition to arterial hypertension, are evidenced by the available clinical and laboratory data? Justify the answer.
2. What could cause these forms of pathology and what is their relationship?
3. What are the main mechanisms of their development, as well as the patient's symptoms?
4. Is there a pathogenetic connection between the form of pathology you identified in the patient and the development of a leg ulcer? If yes, then name and describe the main links of this dependence. If not, then explain the mechanism of ulcer development in this case?
Task 4
Patient M., aged 46, a researcher, complains of memory loss, dizziness, pain in the heart, shortness of breath during exercise. Considers himself ill for 3 years. Does not engage in physical labor and physical education. Smokes a lot. He eats well, eats a lot of meat and animal fats, and fruits and vegetables - not enough. Objectively: medium height, hypersthenic. He looks much older than his years. The skin and muscles are flabby. The borders of the heart are enlarged. The tones are muffled. Pulse 86 per minute, rhythmic. AD 140/90 mm. rt. Art. ECG reveals signs of coronary insufficiency. X-ray revealed dilatation of the aortic arch. The content of cholesterol and β-lipoproteins is sharply increased in the blood. The patient was prescribed physiotherapy exercises and a diet rich in vegetables and fruits, with reduced calorie content and restriction of animal fats. In addition, it is recommended to introduce at least 20 g of natural vegetable oil into the daily diet.
Test questions:
1. What are the likely causes and consequences of hypercholesterolemia in this patient?
Test tasks to control the final level of knowledge of students
1. HYPERCHOLESTEROLEMIA MEETS IN THE FOLLOWING PATHOLOGICAL CONDITIONS (3):
1. suprahepatic jaundice
2. atherosclerosis
3. diabetes
4. acute glomerulonephritis
5. lipoid nephrosis
2. CHOOSE RISK FACTORS FOR DEVELOPING ATHEROSCLEROSIS (3)
1. hypotension
2. hypertension
3. diabetes
4. diabetes insipidus
5. obesity
3. THE FOLLOWING CYTOKINES TAKE PART IN THE FORMATION OF ATEROMES (3):
1. interferons
2. interleukin-3
3. interleukin-1
4. tumor necrosis factor-α
5. platelet growth factor
4. INDICATE THE LEVEL OF CHOLESTEROL IN THE BLOOD PLASMA, REFLECTING ITS EXIT FROM THE VASCULAR WALL (A) AND DEPOSIT IN THE VESSEL INTIMA (B)
1. 4.7 mmol/l
2. 5.2 mmol/l
3. 6.1 mmol/l
5. CHOOSE WHICH RATIO OF LIPOPROTEIN FRACTIONS IN THE BLOOD PLASMA PROMOTES THE FORMATION OF ATHEROSCLEROTIC PLAQUES (2):
1. increase in LDL content
2. LDL reduction
3. increase HDL content
4. HDL reduction
5. VLDL reduction
6. IN THE APPEARANCE OF COMPLICATIONS OF ATHEROSCLEROSIS, THE STATE OF “INSTABILITY” OF YOUNG OR “SOFT” ATHEROSCLEROTIC PLAQUES, PREDISPOSED TO TEAR OF THE SHELL, IS IMPORTANT. THIS LEADS TO THE FOLLOWING VIOLATIONS (3):
1. pain syndrome at the site of plaque rupture
2. increase the thrombogenic potential of the blood
3. formation of a parietal thrombus
4. violation of the rheological properties of blood in the systemic circulation
5. aggravation of local hemodynamic disorders
7. THE EFFECT OF ATHEROSCLEROSIS PREVENTION DRUGS MAY BE ASSOCIATED WITH THE FOLLOWING MECHANISMS (2):
1. Decreased blood levels of LDL
2. increased blood levels of LDL
3. increase in the content of VLDL in the blood
4. increase in blood HDL
5. Decreased HDL levels in the blood
8. CAUSES FOR LIPOPROTEIN MODIFICATION ARE(2):
1. glycosylation
2. lipid breakdown under the action of triglyceride lipase
3. cholesterol esterification
4. FRO activation
5. resynthesis of lipoproteins from ketone bodies and proteins
9. "FOAM CELLS" ARE FORMED WHEN THE ACCUMULATION OF LIPID B(2):
1. macrophages
2. lymphocytes
3. neutrophils
4. smooth muscle cells
5. endothelial cells
10. MACROPHAGES ABSORB LIPOPROTEINS WITH PARTICIPATION (2):
1. Receptor for LDL
2. receptor for HDL
3. receptor for cholesterol
4. receptor for VLDL
5. Receptor for phospholipids
11. THE MAIN COMPONENTS OF FIBROUS PLAQUE ARE(1):
1. fibroblasts
2. eosinophils
3. basophils
4. macrophages
12. CHOOSE A SEQUENCE OF CHANGES DURING ATHEROGENESIS (1):
1) migration of macrophages to the focus of lipid accumulation;
2) capture of lipoproteins by macrophages, transformation into "foam cells"
3) release of growth and chemotactic factors for smooth muscle cells
4) damage to the endothelium and the accumulation of lipoproteins in the intima of the arteries
5) activation of collagen and elastin synthesis by smooth muscle cells
6) the formation of a fibrous capsule around the focus of lipid accumulation
A - 4,3,1,2,5,6
B - 4,2,3,1,5,6
B - 2,4,5,1,3,6
13. PRIMARY ATHEROSCLEROTIC CHANGES IN THE ARTERIES (LIPID STRIPS) MAY APPEAR FOR THE FIRST TIME AT AGE (1):
1. up to 10 years 2. 20–25 years 3. 30–35 years
4. 40–45 years old 5. after 50 years old
14. THE MOST COMMON CONSEQUENCES AND COMPLICATIONS OF ATHEROSCLEROSIS ARE (2):
1. arterial thrombosis
2. venous thrombosis
3. insufficiency of the aortic valve
5. heart failure
15. MINIMUM INCREASE IN CHOLESTEROL COEFFICIENT OF ATHEROGENICITY INDICATING A SIGNIFICANT RISK OF ATHEROSCLEROSIS (1):
1. 1 2. 5 3. 4 4. 3 5. 2
16. CHOOSE THE STATEMENTS TRUE FOR THE THROMBOGENIC THEORY (2):
1. Decreased production of nitric oxide by endotheliocytes
2. decrease in the adhesive ability of platelets
3. increase in the production of nitric oxide by endotheliocytes
4. Strengthening the aggregation ability of platelets
5. increase in production of prostacyclin I2
After absorption into the intestinal epithelium free fatty acids and 2-monoglycerides re-form triglycerides and, together with phospholipids and cholesterol, are incorporated into chylomicrons. Chylomicrons are transported with lymph through the thoracic duct into the superior vena cava, thus entering the general circulation.
Inside the chylomicron triglycerides are hydrolyzed by lipoprotein lipase, which leads to the release of fatty acids on the surface of blood capillaries in tissues. This causes the transport of fatty acids into tissues and the subsequent formation of triglyceride-depleted chylomicron residues. These residues then take up the cholesterol esters from high-density lipoproteins, and the particles are rapidly taken up by the liver. This foodborne fatty acid transport system is referred to as the exogenous transport system.
Also exists endogenous transport system, designed for intraorganic transport of fatty acids formed in the body itself. Lipids are transported from the liver to peripheral tissues and vice versa, and are also transported from fat depots to various organs. The transport of lipids from the liver to peripheral tissues involves the coordinated actions of VLDL, intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). VLDL particles, like chylomicrons, consist of a large hydrophobic core formed by triglycerides and cholesterol esters, and a surface lipid layer consisting mainly of phospholipids and cholesterol.
VLDL synthesized in the liver, and the deposition of fat in peripheral tissues is their main function. After entering the bloodstream, VLDL are exposed to lipoprotein lipase, which hydrolyzes triglycerides to free fatty acids. Free fatty acids derived from chylomicrons or VLDL can be used as energy sources, structural components of phospholipid membranes, or converted back into triglycerides and stored in this form. Chylomicron triglycerides and VLDL are also hydrolyzed by liver lipase.
Particles VLDL by hydrolysis of triglycerides, they are converted into denser, smaller cholesterol- and triglyceride-rich residues (LRLRs), which are removed from plasma by hepatic lipoprotein receptors or can be converted to LDL. LDL are the main lipoprotein carriers of cholesterol.
The return from peripheral tissues to the liver is often referred to as reverse cholesterol transport. HDL particles are involved in this process by taking cholesterol from tissues and other lipoproteins and transporting it to the liver for subsequent excretion. Another type of transport that exists between organs is the transfer of fatty acids from fat depots to organs for oxidation.
Fatty acid, obtained mainly as a result of the hydrolysis of triglycerides of adipose tissue, are secreted into the plasma, where they combine with albumin. Albumin-bound fatty acids are transported along a concentration gradient to metabolizing tissues, where they are used primarily as energy sources.
Over the past 20 years, only a few research were devoted to the issue of lipid transport in the perinatal period (the results of these studies are not presented in this publication). There is a clear need for a more detailed study of this problem.
Fatty acids are used as building blocks material in the composition of cell wall lipids, as energy sources, and are also deposited “in reserve” in the form of triglycerides, mainly in adipose tissue. Some omega-6 and omega-3 LCPUFAs are precursors to biologically active metabolites used in cell signaling, gene regulation, and other metabolically active systems.
Role question LCPUFA ARA and DHA in the process of child growth and development is one of critical issues in research conducted in the field of pediatric nutrition over the past two decades.
Lipids are one of the main components of cell membranes. A significant amount of research in the field of lipid physiology is devoted to two fatty acids - ARA and DHA. ARA is found in the composition of cell membranes of all structures of the human body; it is a precursor of the 2nd series eicosanoids, 3rd series leukotrienes, and other metabolites that are involved in cell signaling systems and gene regulation. Research on DHA often points to its structural and functional role in cell membranes.
This fatty acid found in high concentrations in the gray matter of the brain, as well as in the rods and cones of the retina. Studies of phasing out omega-3 fatty acids from animal diets have shown that 22-carbon omega-6 LCPUFAs (eg, 22:5 n-6) are able to structurally but not functionally replace 22:6 n-3. At an inadequate level of 22:6 n-3 in the tissues, visual and cognitive impairments are detected. Changes in the 22:6 n-3 content in tissues have been shown to affect neurotransmitter function, ion channel activity, signaling pathways, and gene expression.
Return to section heading "
3. Transport forms of lipids in the blood: names, composition, places of formation, significance.
The insolubility or very low solubility of fats in water necessitates the existence of special transport forms for their transfer by blood. The main of these forms are: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL). During electrophoresis, they move at different speeds and are located on electropherograms in the following sequence (from the start): chylomicrons (XM), VLDL (pre-β), LDL (β) and HDL (α-).
Lipoproteins are the smallest globular formations: phospholipid molecules are located radially with a hydrophilic part to the surface, hydrophobic to the center. Protein molecules are similarly located in globules. The central part of the globule is occupied by triacylglycerides and cholesterol. The set of proteins is not the same in different lipoproteins. As can be seen from the table, the density of lipoproteins is directly proportional to the protein content and inversely proportional to the triglyceride content.
Chylomicrons are formed in the cells of the intestinal mucosa, VLDL - in the cells of the mucosa and in hepatocytes, HDL - in hepatocytes and blood plasma, LDL - in blood plasma.
Chylomicrons and VLDL transport triacylglycerides, LDL and HDL mainly cholesterol - this follows from the composition of lipoproteins.
4. The principle of classification of enzymes.
Classification:
Oxidoreductase class - catalyze OVR
Transferases - intercellular transfer reactions (A-B + C \u003d A + B-C)
Hydrolases - reactions of hydrolytic cleavage =C-O- and other bonds
Lyases - reactions of non-hydrolytic cleavage with the formation of 2 bonds
Isomerases - reactions of changing the geometric or spatial structure of a molecule
Ligases (synthetases) - reactions of the connection of 2 molecules, accompanied by the hydrolysis of macroergs.
Ticket 21
1. Biological oxidation: chemistry, types, localization in the cell. Significance for the body.
2. Gluconeogenesis: substrates, relationship with glycolysis (Corey cycle), localization, biological significance. Regulation.
3. Vitamin D: the most important sources of the vitamin, the coenzyme form (if known), processes leading to the formation of the active form; biochemical processes in which it participates; biochemical changes in hypovitaminosis.
4. Enzyme catalyzes the cleavage of a peptide bond in a protein molecule. Name the class and subclass of the enzyme.
Answer:
1 ) Biological oxidation - a process during which oxidizing substrates lose protons and electrons, i.e. are hydrogen donors, intermediate carriers are acceptor-donors, and oxygen is the final hydrogen acceptor.
Oxidation can be realized in 3 ways: by adding oxygen to a carbon atom in the substrate, by splitting off hydrogen, or by losing an electron. In the cell, oxidation proceeds in the form of a successive transfer of hydrogen and electrons from the substrate to oxygen. Oxygen plays the role of an oxidizing agent.
Oxidative reactions proceed with the release of energy.
The reduction of an oxygen atom upon interaction with a pair of protons and electrons leads to the formation of a water molecule. Therefore, oxygen is consumed in the process of biological oxidation. The cell, tissue or organ in which the substrate is oxidized consumes oxygen. The consumption of oxygen by tissues is called tissue respiration.
The concepts of biological oxidation and tissue respiration are unambiguous when it comes to biological oxidation with the participation of oxygen. This type of oxidation can also be called aerobic oxidation.
Along with oxygen, the role of the final acceptor in the hydrogen transfer chain can be played by compounds that are reduced in this case to dihydrosubducts.
Biological oxidation is the dehydrogenation of a substrate with the help of intermediate hydrogen carriers and its final acceptor. If oxygen acts as the final acceptor - aerobic oxidation or tissue respiration, if the final acceptor is not oxygen - anaerobic oxidation.
2) Gluconeogenesis- synthesis of glucose from non-carbohydrate precursors. The main precursors are pyruvate and lactate, the intermediate ones are TCA metabolites, glucogenic (glucoplastic) amino acids, and glycerol.
The nodal point of glucose synthesis is the conversion of pyruvate to phosphoenolpyruvate (PEP).
Pyruvate is carboxylated by pyruvate carboxylase at the expense of ATP energy, the reaction is carried out in mitochondria"
CH,-CO-COOH + CO, -------------- "NOOS-CH.-CO-COOH
Pyruvate ATP ADP + (P) Oxaloacetate
Phosphorylating decarboxylation then occurs, catalyzed by phosphoenolpyruvate carboxykinase:
HOOC-CH-CO-COOH + GTP --- HC=C-COOH + GDP + COd Oxaloacetate
The further pathway for the formation of G-6-P is the reverse pathway of glycolysis, catalyzed by the same enzymes, but in the opposite direction. The only exception is the conversion of fructose-1,6-diphosphate to fructose-6-phosphate catalyzed by fructose diphosphatase.
A number of amino acids (asparagine, aspartic acid, tyrosine, phenylalanine, threonine, valine, methionine, isoleucine, glutamine, proline, histidine and arginine) are converted in one way or another into the TCA metabolite - fumaric acid, and the latter into oxaloacetate. Others (alanine, serine, cystine and glycine) - in pyruvate. Partially, asparagine and aspartic acid are converted directly to oxaloacetate.
Glycerol is involved in the processes of gluconeogenesis at the stage of 3-PHA, lactate is oxidized to pyruvate. On fig. 57 is a diagram of gluconeogenesis.
Glucose enters the cells from the intestine, where it undergoes phosphorylation with the formation of G-6-P. It can be converted in one of four ways" into free glucose; into glucose-1-phosphate, which is used in the synthesis of glycogen; it is involved in the main pathway, where it breaks down to CO, with the release of energy stored in the form of ATP, or to lactate; to be involved in PPP, where the synthesis of NADP Hg, which serves as a source of hydrogen for reductive syntheses, and the formation of ribose-5-phosphate, which is used in the synthesis of DNA and RNA, are carried out.
Glucose is stored in the form of glycogen, deposited in the liver, muscles, and kidneys. When glycogen is consumed due to intensive energy consumption or lack of carbohydrates in the diet, the content of glucose and glycogen can be replenished due to synthesis from non-carbohydrate components of metabolism, i.e. by gluconeogenesis.
3) Vitamin D - calciferol, antirachitic factor. With food (liver, butter, milk, fish oil) it comes in the form of precursors. The main one is 7-dehydrocholesterol, which after exposure to UV in the skin turns into cholecalciferol (vitamin D3). Vitamin D3 is transported to the liver, where it is hydroxylated at position 25 to form 25-hydroxycholecalciferol. This product is transported to the kidneys where it is hydroxylated to its active form. The appearance of the active form of cholecalciferol in the kidney is controlled by the parathyroid hormone of the parathyroid glands.
Entering the intestinal mucosa with the bloodstream, the active form of the vitamin causes the conversion of the precursor protein into a calcium-binding protein, which accelerates the absorption of calcium ions from the intestinal lumen. Similarly, calcium reabsorption in the renal tubules is accelerated.
Deficiency can occur with vitamin D deficiency in food, insufficient solar exposure, kidney disease and insufficient production of parathyroid hormone.
Vitamin D deficiency results in decreased levels of calcium and phosphorus. bone tissue. As a result - deformation of the skeleton - rickety rosary, X-shaped legs, a bird's chest. The disease in children is rickets.
| " |
Since lipids are insoluble in water, special transport forms are formed for their transfer from the intestinal mucosa to organs and tissues: chylomicrons (XM), very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL). Directly from the mucosa of the small intestine, the transport of absorbed and resynthesized lipids is carried out as part of chylomicrons. XM are protein-lipid complexes with a diameter of 100 to 500 nm, which, due to their relatively large size, cannot immediately penetrate into the blood. First, they enter the lymph and in its composition enter the thoracic lymphatic duct, and then into the superior vena cava and are carried with blood throughout the body. Therefore, after ingestion of fatty foods, the blood plasma becomes cloudy within 2 to 8 hours. Chemical composition HM: The total lipid content is 97-98%; their composition is dominated by TAG (up to 90%), the content of cholesterol (X), its esters (EC) and phospholipids (PL) in total accounts for -7-8%. The content of the protein stabilizing the structure of HM is 2-3%. Thus, HM is a transport form of "food" or exogenous fat. in the capillaries various bodies and tissues (adipose, liver, lungs, etc.) contains lipoprotein lipase (LP-lipase), which breaks down the TAG of chylomicrons to glycerol and fatty acids. In this case, the blood plasma becomes clear, i.e. ceases to be cloudy, which is why LP-lipase is called the “clearing factor”. It is activated by heparin, which is produced by mast cells of the connective tissue in response to hyperlipidemia. TAG cleavage products diffuse into adipocytes, where they are deposited or enter other tissues to cover energy costs. In fat depots, as the body needs energy, TAG is decomposed to glycerol and fatty acids, which, in combination with blood albumins, are transported to peripheral cells of organs and tissues.
Remnant HMs (i.e., remaining after TAG cleavage) enter hepatocytes and are used by them to build other transport forms of lipids: VLDL, LDL, HDL. Their composition is supplemented with TAG fatty acids, phospholipids, cholesterol, cholesterol esters, sphingosine-containing lipids synthesized in the liver "de novo". The size of HM and their chemical composition change as they move along the vascular bed. CMs have the lowest density compared to other lipoproteins (0.94) and the largest sizes (their diameter is ~ 100 nm). The higher the density of the LP particles, the smaller their size. The diameter of HDL is the smallest (10 - 15 nm), and the density fluctuates in the range of 1.063 - 1.21.
VLDL are formed in the liver, contain 55% TAG in their composition, so they are considered a transport form of endogenous fat. VLDLP transport TAG from liver cells to the cells of the heart, skeletal muscles, lungs and other organs, which have on their surface the enzyme LP - lipase.
LP - lipase breaks down VLDL TAG to glycerol and fatty acids, converting VLDL to LDL (VLDL - TAG = LDL). LDL can also be synthesized "de novo" in hepatocytes. Cholesterol predominates in their composition (~ 50%), their function is the transport of cholesterol and phospholipids to peripheral cells of organs and tissues, which have specific receptors for LDL on their surface. Cholesterol and phospholipids transported by LDL are used to build membrane structures in peripheral cells. Absorbed by various cells, LDL carry information about the content of cholesterol in the blood and determine the rate of its synthesis in cells. HDL is synthesized mainly in the liver cells. These are the most stable forms of lipoproteins, tk. contain ~50% protein. They are characterized by high content of phospholipids (~20%) and low content of TAG (~3%). HDL (see Table No. 1) are synthesized by hepatocytes in the form of flat discs. Circulating in the blood, they absorb excess cholesterol from various cells, vessel walls and, returning to the liver, acquire a spherical shape. THEN. , the main biological function of HDL is the transport of cholesterol from peripheral cells to the liver. In the liver, excess cholesterol is converted into bile acids.
Table number 1. Chemical composition of transport lipoproteins (%).