Transport of lipids in the human body. Transport of lipids in the blood. Biological significance of fatty acids
Department of Biochemistry
LECTURE COURSE
FOR GENERAL BIOCHEMISTRY
for 2nd year students
treatment and prophylactic
faculty
Module 4. Biochemistry of lipids
Ekaterinburg,
2013
LECTURE
Topic: Digestion and absorption of lipids. Transport of lipids in the body.
Lipoprotein exchange. Dyslipoproteinemia.
Lipids- this is a group of organic substances diverse in structure, which are united by a common property - solubility in non-polar solvents.
LIPID CLASSIFICATION
According to their ability to hydrolyze lipids are divided into saponifiable (two or more component) and unsaponifiable (single component).
Saponifiable lipids in an alkaline environment are hydrolyzed to form soaps, they contain fatty acids and alcohols glycerol (glycerolipids) or sphingosine (sphingolipids). According to the number of components, saponifiable lipids are divided into simple (consist of 2 classes of compounds) and complex (consist of 3 or more classes).
Simple lipids include:
1) wax (ester of higher monohydric alcohol and fatty acid);
2) triacylglycerides , diacylglycerides, monoacylglycerides (an ester of glycerol and fatty acids). In a person weighing 70 kg, TG is about 10 kg.
3) ceramides (ester of sphingosine and C18-26 fatty acid) - are the basis of sphingolipids;
Complex lipids include:
1) phospholipids (contain phosphoric acid):
a) phosphoglycerolipids (ester of glycerol and 2 fatty acids, contains phosphoric acid and amino alcohol) - phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol;
b) cardiolipins (2 phosphatidic acids connected through glycerol);
c) plasmalogens (an ester of glycerol and a fatty acid, contains an unsaturated monohydric higher alcohol, phosphoric acid and amino alcohol) - phosphatidalethanolamines, phosphatidalserins, phosphatidalcholines;
d) sphingomyelins (ester of sphingosine and C18-26 fatty acid, contains phosphoric acid and amino alcohol - choline);
2) glycolipids (derivatives of sphingosine containing carbohydrates):
a) cerebrosides (ester of sphingosine and C18-26 fatty acid, contains hexose: glucose or galactose);
b) sulfatides (an ester of sphingosine and C18-26 fatty acid, contains hexose (glucose or galactose) to which sulfuric acid is attached in the 3 position). Many in white matter;
c) gangliosides (ester of sphingosine and C18-26 fatty acid, contains oligosaccharide from hexoses and sialic acids). Found in ganglion cells
Unsaponifiable lipids include:
1. steroids;
2. fatty acids (structural component of saponifiable lipids),
3. vitamins A, D, E, K;
4. terpenes (hydrocarbons, alcohols, aldehydes and ketones with several isoprene units).
LIPID DIGESTION
digestion is hydrolysis. nutrients to their assimilated forms.
Only 40-50% of dietary lipids are completely broken down, from 3% to 10% of dietary lipids are absorbed unchanged.
Since lipids are insoluble in water, their digestion and absorption has its own characteristics and proceeds in several stages:
1) Lipids of solid food under mechanical action and under the influence of bile surfactants are mixed with digestive juices to form an emulsion (oil in water). The formation of an emulsion is necessary to increase the area of action of enzymes, because. they only work in the aqueous phase. Liquid food lipids (milk, broth, etc.) enter the body immediately in the form of an emulsion;
2) Under the action of lipases of digestive juices, the lipids of the emulsion are hydrolyzed with the formation of water-soluble substances and simpler lipids;
3) Water-soluble substances isolated from the emulsion are absorbed and enter the blood. The simpler lipids isolated from the emulsion combine with bile components to form micelles;
4) Micelles ensure the absorption of lipids into intestinal endothelial cells.
Oral cavity
In the oral cavity, mechanical grinding of solid food and wetting it with saliva (pH=6.8) takes place.
In infants, hydrolysis of triglycerides begins here with short and medium fatty acids, which come with liquid food in the form of an emulsion. Hydrolysis is carried out by lingual triglyceride lipase (“tongue lipase”, TGL), which is secreted by the Ebner glands located on the dorsal surface of the tongue.
Stomach
Since "tongue lipase" acts in the pH range of 2-7.5, it can function in the stomach for 1-2 hours, breaking down up to 30% of triglycerides with short fatty acids. In infants and children younger age it actively hydrolyzes milk TG, which contain mainly fatty acids with short and medium chain lengths (4-12 C). In adults, the contribution of tongue lipase to TG digestion is negligible.
Produced in the chief cells of the stomach gastric lipase , which is active at neutral pH, characteristic of the gastric juice of infants and young children, and is not active in adults (pH of gastric juice ~ 1.5). This lipase hydrolyzes TG, mainly cleaving off fatty acids at the third carbon atom of glycerol. FAs and MGs formed in the stomach are further involved in the emulsification of lipids in the duodenum.
Small intestine
The main process of lipid digestion occurs in the small intestine.
1. Lipid emulsification(mixing of lipids with water) occurs in the small intestine under the action of bile. Bile is synthesized in the liver, concentrated in the gallbladder and released into the lumen after eating fatty foods. duodenum(500-1500 ml/day).
Bile it is a viscous yellow-green liquid, has a pH = 7.3-8.0, contains H 2 O - 87-97%, organic matter(bile acids - 310 mmol / l (10.3-91.4 g / l), fatty acids - 1.4-3.2 g / l, bile pigments - 3.2 mmol / l (5.3-9 .8 g / l), cholesterol - 25 mmol / l (0.6-2.6) g / l, phospholipids - 8 mmol / l) and mineral components (sodium 130-145 mmol / l, chlorine 75-100 mmol /l, HCO 3 - 10-28 mmol/l, potassium 5-9 mmol/l). Violation of the ratio of bile components leads to the formation of stones.
bile acids(cholanic acid derivatives) are synthesized in the liver from cholesterol (cholic and chenodeoxycholic acids) and formed in the intestine (deoxycholic, lithocholic, etc. about 20) from cholic and chenodeoxycholic acids under the action of microorganisms.
In bile, bile acids are present mainly in the form of conjugates with glycine (66-80%) and taurine (20-34%), forming paired bile acids: taurocholic, glycocholic, etc.
Bile salts, soaps, phospholipids, proteins and the alkaline environment of bile act as detergents (surfactants), they reduce the surface tension of lipid droplets, as a result, large droplets break up into many small ones, i.e. emulsification takes place. Emulsification is also facilitated by intestinal peristalsis and CO 2 released during the interaction of chyme and bicarbonates: H + + HCO 3 - → H 2 CO 3 → H 2 O + CO 2.
2. Hydrolysis of triglycerides carried out by pancreatic lipase. Its pH optimum is 8, it hydrolyzes TG predominantly in positions 1 and 3, with the formation of 2 free fatty acids and 2-monoacylglycerol (2-MG). 2-MG is a good emulsifier.
28% of 2-MG is converted into 1-MG by isomerase. Most of the 1-MG is hydrolyzed by pancreatic lipase to glycerol and a fatty acid.
In the pancreas, pancreatic lipase is synthesized together with the protein colipase. Colipase is formed in an inactive form and is activated in the intestine by trypsin by partial proteolysis. Colipase, with its hydrophobic domain, binds to the surface of the lipid droplet, while its hydrophilic domain promotes the maximum approach of the active center of pancreatic lipase to TG, which accelerates their hydrolysis.
3. Hydrolyslecithin occurs with the participation of phospholipases (PL): A 1, A 2, C, D and lysophospholipase (lysoPL).
As a result of the action of these four enzymes, phospholipids are cleaved to free fatty acids, glycerol, phosphoric acid and an amino alcohol or its analogue, for example, the amino acid serine, however, part of the phospholipids is cleaved with the participation of phospholipase A2 only to lysophospholipids and in this form can enter the intestinal wall.
PL A 2 is activated by partial proteolysis with the participation of trypsin and hydrolyzes lecithin to lysolecithin. Lysolecithin is a good emulsifier. LysoFL hydrolyzes part of lysolecithin to glycerophosphocholine. The remaining phospholipids are not hydrolyzed.
4. Cholesterol hydrolysis esters to cholesterol and fatty acids is carried out by cholesterol esterase, an enzyme of the pancreas and intestinal juice.
5. Micelle formation
Water-insoluble hydrolysis products (long-chain fatty acids, 2-MG, cholesterol, lysolecithins, phospholipids) together with bile components (bile salts, cholesterol, PL) form structures in the intestinal lumen called mixed micelles. Mixed micelles are built in such a way that the hydrophobic parts of the molecules face the inside of the micelles (fatty acids, 2-MG, 1-MG), and the hydrophilic parts (bile acids, phospholipids, cholesterol) face the outside, so the micelles dissolve well in the aqueous phase of the contents of the small intestine. The stability of micelles is provided mainly by bile salts, as well as monoglycerides and lysophospholipids.
Digestion regulation
Food stimulates secretion from the cells of the small intestine mucosa into the blood cholecystokinin (pancreozymin, peptide hormone). It causes the release of bile from the gallbladder and pancreatic juice from the pancreas into the lumen of the duodenum.
Acidic chyme stimulates secretion from the cells of the small intestine mucosa into the blood secretin (peptide hormone). Secretin stimulates the secretion of bicarbonate (HCO 3 -) into the pancreatic juice.
LIPID METABOLISM IN ENTEROCYTES
Lipids enter enterocytes both from the intestinal lumen and from tissues. Most of the lipids that enter the enterocyte undergo resynthesis.
1. 1-MG hydrolyzed by intestinal lipase to glycerol and fatty acids.
2. Short chain fatty acids, PL (except lecithin) and part of glycerol without changes are sent from the enterocyte to the blood.
3. Long chain endogenous and exogenous fatty acids under the action of acyl-CoA synthetase (thiokinase) are activated, forming Acyl ~ CoA:
RCOOH + HS-CoA + ATP → Acyl~CoA + AMP + FFn
Lipoprotein metabolism
Lipoproteins (LP)- These are supramolecular complexes of a spherical shape, consisting of lipids, proteins and carbohydrates. LPs have a hydrophilic shell and a hydrophobic core. The hydrophilic shell includes proteins and amphiphilic lipids - PL, CS. The hydrophobic core includes hydrophobic lipids - TG, cholesterol esters, etc. LPs are highly soluble in water.
Several types of LP are synthesized in the body, they differ chemical composition, are formed in different places and transport lipids in different directions.
LP is separated using:
1) electrophoresis, by charge and size, on α-LP, β-LP, pre-β-LP and HM;
2) centrifugation, by density, for HDL, LDL, LPP, VLDL and HM.
The ratio and amount of LP in the blood depends on the time of day and on nutrition. In the postabsorptive period and during fasting, only LDL and HDL are present in the blood.
The main types of lipoproteins
Composition, % | HM | VLDL (pre-β-LP) | LPPP (pre-β-LP) | LDL (β-LP) | HDL (α-LP) |
Squirrels | |||||
FL | |||||
XC | |||||
EHS | |||||
TG | |||||
Density, g/ml | 0,92-0,98 | 0,96-1,00 | 0,96-1,00 | 1,00-1,06 | 1,06-1,21 |
Diameter, nm | >120 | 30-100 | 30-100 | 21-100 | 7-15 |
Functions | Transport of exogenous dietary lipids to tissues | Transport of endogenous liver lipids to tissues | Transport of cholesterol in tissues | Removal of excess cholesterol from tissues Donor apo A, C, E | |
Place of education | enterocyte | hepatocyte | in the blood from VLDL | in blood from LPP | hepatocyte |
apo | B-48, C-II, E | B-100, S-II, E | B-100, E | B-100 | A-I C-II, E, D |
Norm in the blood | < 2,2 ммоль/л | 0.9-1.9 mmol/l |
Apoproteins
Proteins that make up LP are called apoproteins (apoproteins, apo). The most common apoproteins include: apo A-I, A-II, B-48, B-100, C-I, C-II, C-III, D, E. Apoproteins can be peripheral (hydrophilic: A-II, C-II, E) and integral (have a hydrophobic area: B-48, B-100). Peripheral apos pass between LPs, while integral ones do not. Apoproteins perform several functions:
Apoprotein | Function | Place of education | Localization |
A-I | liver | HDL | |
A-II | LCAT activator, EHS formation | HDL, HM | |
B-48 | enterocyte | HM | |
B-100 | Structural (LP synthesis), receptor (LP phagocytosis) | liver | VLDL, LPP, LDL |
C-I | LCAT activator, EHS formation | Liver | HDL, VLDL |
C-II | LPL activator, stimulates the hydrolysis of TG into LP | Liver | HDL → HM, VLDL |
C-III | LPL inhibitor, inhibits the hydrolysis of TG into LP | Liver | HDL → HM, VLDL |
D | Cholesterol ester transfer (CET) | Liver | HDL |
E | Receptor, phagocytosis of LP | liver | HDL → HM, VLDL, LPPP |
lipid transport enzymes
Lipoprotein lipase (LPL)(EC 3.1.1.34, LPL gene, about 40 defective alleles) is associated with heparan sulfate located on the surface of endothelial cells of blood vessel capillaries. It hydrolyzes TG in the composition of LP to glycerol and 3 fatty acids. With the loss of TG, HM turn into residual HM, and VLDL increase their density to LDL and LDL.
Apo C-II LP activates LPL, and LP phospholipids are involved in the binding of LPL to the surface of LP. LPL synthesis is induced by insulin. Apo C-III inhibits LPL.
LPL is synthesized in the cells of many tissues: fat, muscle, lungs, spleen, cells of the lactating mammary gland. It is not in the liver. LPL isoenzymes of different tissues differ in Km value. In adipose tissue, LPL has a Km 10 times greater than in the myocardium; therefore, fatty acids are absorbed into adipose tissue only with an excess of TG in the blood, and the myocardium is constantly, even with a low concentration of TG in the blood. Fatty acids in adipocytes are used for the synthesis of triglycerides, in the myocardium as an energy source.
Hepatic lipase located on the surface of hepatocytes, it does not act on mature HM, but hydrolyzes triglyceride into LPPP.
Lecithin: cholesterol acyl transferase (LCAT) be in HDL, it transfers acyl from lecithin to cholesterol with the formation of ECS and lysolecithin. It is activated by apo A-I, A-II and C-I.
lecithin + cholesterol → lysolecithin + ECS
ECS is immersed in the core of HDL or transferred with the participation of apo D to other LPs.
NORMAL VALUES
CHYLOMICRON EXCHANGE
Lipids resynthesized in enterocytes are transported to tissues as part of HM.
· The formation of HM begins with the synthesis of apo B-48 on ribosomes. Apo B-48 and B-100 share a common gene. If only 48% of the information is copied from the gene to mRNA, then apo B-48 is synthesized from it, if 100%, then apo B-100 is synthesized from it.
· With ribosomes, apo B-48 enters the lumen of the ER, where it is glycosylated. Then, in the Golgi apparatus, apo B-48 is surrounded by lipids and the formation of "immature", nascent HM occurs.
By exocytosis, nascent HMs are released into the intercellular space, enter the lymphatic capillaries and through the lymphatic system, through the main thoracic lymphatic duct enter the bloodstream.
· Apo E and C-II are transferred from HDL to nascent HM in the lymph and blood, and HM turns into “mature” ones. XM are quite large, so they give the blood plasma an opalescent, milky appearance. Under the action of LPL, TH HM is hydrolyzed into fatty acids and glycerol. The main mass of fatty acids penetrates the tissue, and glycerol is transported with blood to the liver.
· When the amount of TG in HM decreases by 90%, they decrease in size, and apo C-II is transferred back to HDL, "mature" HM turns into "residual" remnant HM. Remnant HMs contain phospholipids, cholesterol, fat-soluble vitamins, and apo B-48 and E.
· Through the LDL receptor (uptake of apo E, B100, B48), remnant CMs are captured by hepatocytes. By endocytosis, residual CM enter the cells and are digested in lysosomes. HM disappear from the blood within a few hours.
HDL METABOLISM
HDL perform 2 main functions: they supply apo to other lipoproteins in the blood and participate in the so-called "reverse cholesterol transport". HDL is synthesized in the liver and in small amounts in the small intestine. nascent HDL . They are disc-shaped, small in size and contain a high percentage of proteins and phospholipids. In the liver, apoproteins A, E, C-II, LCAT are included in HDL. In the blood, apo C-II and apo E are transferred from HDL to HM and VLDL. nascent HDL practically do not contain cholesterol and TG and are enriched with 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 is the LCAT enzyme - lecithin: cholesterol acyltransferase. This enzyme converts cholesterol to ECS. The reaction is activated by apo A-I, which is part of HDL.
EChS moves inside HDL. Thus, HDL are enriched with ECS. HDL increases in size, from disc-shaped small particles turn into spherical particles, which are called HDL 3, or "mature HDL" . HDL 3 partially exchange ECS for TG contained in VLDLP, LPP and HM. This transfer involves the “protein that carries cholesterol esters” - apo D. Thus, part of the ECS is transferred to VLDL, LDL, and HDL 3 due to the accumulation of triglycerides increase in size and turn into HDL 2 .
Part of HDL is taken up by liver cells, interacting with HDL-specific apo A-1 receptors . On the surface of liver cells, PL and TG LPP, HDL 2 are hydrolyzed hepatic lipase , which destabilizes the structure of the LP surface and promotes the diffusion of cholesterol into hepatocytes. HDL 2 is then converted back to HDL 3 and returned to the bloodstream.
HDL DISORDERS
Tenji disease
Aborigines of the island of Tenji are sick. Hereditary defect of apo A, HDL is not synthesized. The transport of excess cholesterol from tissues to the liver is disrupted. In the blood there is a low level of cholesterol, PL, a lot of TG. Macrophages phagocytize excess cholesterol in tissues with the formation of xanthoma. The accumulation of cholesterol in the liver, spleen and other lymphoid organs causes hepatosplenomegaly and lymphadenopathy. Cataracts, polyneuropathy, and rhinitis may develop. Tonsils due to cholesterol deposits are colored orange-yellow.
Bibliography
Bersenev Alexey Vyacheslavovich. PhD thesis: Transplantation of embryonic liver cells and bone marrow stem cells for the correction of dyslipidemia and early stages of atherogenesis. M.: 2003.
LECTURE #13
Development of adipose tissue
Adipose tissue develops from mesenchyme from 30 weeks embryonic development. The mesenchymal cell turns into a lipoblast, which in turn turns into a mature fat cell - an adipocyte. There are two periods of active increase in the number of adipocytes: (1) the period of embryonic development and (2) the period of puberty. In other periods of a person's life, progenitor cells usually do not multiply. The accumulation of fat occurs only by increasing the size of already existing fat cells. If the amount of fat in a cell reaches a critical mass, progenitor cells receive a signal and begin to multiply, giving rise to new fat cells. A lean adult has about 35 billion fat cells, a severely obese person has up to 125 billion, that is, 4 times more. The newly formed fat cells are not subject to reverse development, and remain for life. If a person loses weight, then they only decrease in size. |
CHEMICAL COMPOSITION OF WHITE ADIPOSE TISSUE
Adipose tissue contains 65-85% TG, 22% water, 5.8% protein, 15 mmol/kg potassium. Of the fatty acids, 42-51% are oleic, 22-31% are palmitic, 5-14% are palmitooleic, 3-5% are myristic, and 1-5% are linoleic acids.
The composition of adipose tissue depends on the area of the body, the depth of the layer; it may also differ somewhat in individual individuals. The content of water and protein is especially subject to changes. The deeper under the surface of the skin the fat is located, the more it contains saturated acids. In newborns, saturated fats in all layers are contained in the same amount.
FEATURES OF WHITE ADIPOSE TISSUE METABOLISM
energy exchange low, predominantly anaerobic, the tissue consumes little oxygen. The energy of ATP is mainly spent on the transport of fatty acids across cell membranes (with the participation of carnitine).
Protein metabolism is low, proteins are synthesized by adipocytes mainly for their own needs. Leptin, proteins of the acute phase of inflammation (α1-acid glycoprotein, haptoglobin), components of the complement system (adipsin, complement C3, factor B), interleukins are synthesized for export in adipose tissue.
carbohydrate metabolism. Low, catabolism predominates. Carbohydrate metabolism in adipose tissue is closely related to lipid metabolism.
lipid metabolism
Adipose tissue ranks second in lipid metabolism after the liver. Here the reactions of lipolysis and lipogenesis take place.
Lipogenesis. In adipose tissue, lipid synthesis occurs during the absorptive period along the glycerophosphate pathway. The process is stimulated by insulin.
Stages of lipogenesis:
1. Under the action of insulin on ribosomes, the synthesis of LPL is stimulated.
2. LPL exits the adipocyte and is fixed on the surface of the capillary wall with heparan sulfate.
3. LPL hydrolyzes TG as part of lipoproteins
4. The resulting glycerol is carried away by the blood to the liver.
5. Fatty acids from the blood are transported to the adipocyte.
6. In addition to exogenous fatty acids coming from outside, fatty acids are synthesized in the adipocyte from glucose. The process is stimulated by insulin.
7. Fatty acids in the adipocyte under the action of Acyl-CoA synthetase are converted into Acyl-CoA.
7. Glucose enters the adipocyte with the participation of GLUT-4 (insulin activator).
8. In the adipocyte, glucose enters into glycolysis with the formation of FDA (insulin activator).
9. In the cytoplasm of FDA, glycerol-ph DG is reduced to glycerophosphate:
Since there is no glycerokinase in adipose tissue, glycerophosphate is formed only from glucose (not from glycerol).
10. In mitochondria, glycerophosphate is converted into lysophosphatide by the action of glycerol phosphate acyltransferase:
11. In mitochondria, lysophosphatide is converted into phosphatide by the action of lysophosphatide acyltransferase:
11. Phosphatide under the action of phosphotidate phosphohydrolase is converted into 1,2-DG:
12. 1,2-DG is converted into TG by the action of acyltransferase:
13. TG molecules combine into large fat droplets.
2. Lipolysis. Lipolysis in adipose tissue is activated when there is a deficiency of glucose in the blood (post-absorption period, fasting, physical activity). The process is stimulated by glucagon, adrenaline, to a lesser extent growth hormone and glucocorticoids.
As a result of lipolysis, the concentration of free fatty acids in the blood increases by 2 times.
FEATURES OF METABOLISM OF BROWN ADIPOSE TISSUE
Energy exchange. The tissue consumes a lot of oxygen, actively oxidizes glucose and fatty acids. Energy exchange is high. At the same time, ATP is formed only in reactions of substrate phosphorylation (2 glycolysis reactions, 1 TCA reaction). The reason is the uncoupling of oxidation and phosphorylation processes in mitochondria by the protein thermogenin (RB-1), low activity of ATP synthetase, lack of respiratory control by ADP. In brown adipose tissue, all the energy generated during oxidation is dissipated in the form of heat (thermogenesis).
Thermogenesis in brown adipose tissue is activated by supercooling of the SNS, as well as with an excess of lipids in the blood, under the action of leptin. Due to this, body temperature rises and the concentration of lipids in the blood decreases. The absence of brown adipose tissue in adults is responsible for 10% of all cases of obesity.
LECTURE #14
The structure of fatty acids
fatty acids(FA) - called carboxylic acids, which are formed during the hydrolysis of saponifiable lipids.
Basically, fatty acids include higher carboxylic acids (containing 12 or more C atoms). Such fatty acids are water insoluble; they are transported in the blood with the help of albumins, and in cells - with the help of Z-proteins.
Human and animal FAs have some structural features: 1) they are monocarboxylic; 2) contain an even number of C atoms, the most common length is from 16 to 18 C atoms; 3) the carbon skeleton is unbranched; 4) are saturated and unsaturated (monounsaturated and polyunsaturated); five). double bonds are not conjugated (separated by methylene bridges) and have a cis conformation.
№ | Fatty acid | LCD index | ∆ LCD | ω LCD |
Lauric | 12:0 | |||
Myristic | 14:0 | |||
palmitic | 16:0 | |||
Palmitoleic | 16:1 | ∆9 | ω9 | |
Stearic | 18:0 | |||
Oleic | 18:1 | ∆9 | ω9 | |
Linoleic | 18:2 | ∆9,12 | ω6 | |
Linolenic | 18:3 | ∆9,12,15 | ω3 | |
Octadecatetraenoic | 18:4 | ∆5,8,11,14 | ω3 | |
Arachinoic | 20:0 | |||
Gadoleic | 20:1 | ∆9 | ω9 | |
Eicosatriene | 20:3 | ∆8,11,14 | ω6 | |
Arachidonic | 20:4 | ∆5,8,11,14 | ω6 | |
Eicosapentaenoic | 20:5 | ∆5,8,11,14,17 | ω3 | |
Begenovaya | 22:0 | |||
Erucovaya | 22:1 | ∆13 | ω9 | |
Andrenova | 22:4 | ∆9,12,15,18 | ω6 | |
Docosapentaenoic | 22:5 | ∆4,7,10,13,16 | ω6 | |
Docosahexaenoic | 22:6 | ∆4,7,10,13,16,19 | ω3 | |
Lignoceric | 24:0 | |||
neuron | 24:1 | ∆15 | ω9 | |
Cerebronic | 24:0 | α-hydroxy FA |
∆ LC are the numbers of C atoms that have double bonds.
ω LC is the number of C atoms from the last double bond to the end of the chain.
Biological significance of fatty acids
- polyene fatty acids (arachidonic, eicosapentaenoic, eicosatriene) are used for the synthesis of biologically active substances - eicosanoids (prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipoxins).
- FAs are oxidized under aerobic conditions with the formation of ATP;
- FAs are a structural component of saponifiable lipids: waxes, glycerolipids, sphingolipids, cholesterol esters;
CATABOLISM OF FATTY ACIDS
In living organisms, FA catabolism proceeds as in enzymatic so in non-enzymatic reactions.
Enzymatic catabolism of fatty acids occurs mainly in β-oxidation reactions. Side pathways include enzymatic α- and ω-oxidation of fatty acids, as well as degradation of fatty acids in peroxisomes. Although these side pathways are quantitatively less important, their disruption can lead to severe disease.
Non-enzymatic catabolism of fatty acids occurs in the reactions of lipid peroxidation (LPO).
β-oxidation of fatty acids
β-oxidation- a specific pathway of catabolism of fatty acids with an unbranched medium and short hydrocarbon chain. β-oxidation proceeds in the mitochondrial matrix, in which 2 C atoms in the form of Acetyl-CoA are sequentially separated from the C end of the FA. β-oxidation of fatty acids occurs only under aerobic conditions and is a source of a large amount of energy.
β-oxidation of fatty acids actively proceeds in red skeletal muscles, cardiac muscle, kidneys, and liver. FAs do not serve as a source of energy for nerve tissues, since FAs do not pass through the blood-brain barrier, like other hydrophobic substances.
β-oxidation of fatty acids increases in the post-absorptive period, during fasting and physical work. At the same time, the concentration of fatty acids in the blood increases as a result of the mobilization of fatty acids from adipose tissue.
LCD activation
Activation of fatty acids occurs as a result of the formation of a macroergic bond between fatty acids and HSCoA with the formation of Acyl-CoA. The reaction is catalyzed by the enzyme Acyl-CoA synthetase:
RCOOH + HSKoA + ATP → RCO~SCoA + AMP + PPn
Pyrophosphate is hydrolyzed by the enzyme pyrophosphatase: H 4 P 2 O 7 + H 2 O → 2H 3 PO 4
Acyl-CoA synthetases are found both in the cytosol (on the outer membrane of mitochondria) and in the mitochondrial matrix. These enzymes differ in their specificity for fatty acids with different hydrocarbon chain lengths.
Transport LCD
The transport of fatty acids into the mitochondrial matrix depends on the length of the carbon chain.
FAs with short and medium chain lengths (from 4 to 12 C atoms) can penetrate into the mitochondrial matrix by diffusion. These fatty acids are activated by acyl-CoA synthetases in the mitochondrial matrix.
Long-chain fatty acids are first activated in the cytosol (by acyl-CoA synthetases on the outer mitochondrial membrane), and then transferred to the mitochondrial matrix by a special transport system using carnitine. Carnitine comes from food or is synthesized from lysine and methionine with the participation of vitamin C.
In the outer membrane of mitochondria, the enzyme carnitine acyltransferase I (carnitine palmitoyl transferase I) catalyzes the transfer of acyl from CoA to carnitine with the formation of acylcarnitine;
Acylcarnitine passes through the intermembrane space to the outer side of the inner membrane and is transported by carnitine acylcarnitine translocase to the inner surface of the inner mitochondrial membrane;
The enzyme carnitine acyltransferase II catalyzes the transfer of acyl from carnitine to intramitochondrial HSCoA with the formation of Acyl-CoA;
Free carnitine is returned to the cytosolic side of the inner mitochondrial membrane by the same translocase.
Reactions β-oxidation of fatty acids
1. β-oxidation begins with the dehydrogenation of acyl-CoA by FAD-dependent Acyl-CoA dehydrogenase with the formation of a double bond (trans) between α- and β-C atoms in Enoyl-CoA. The reduced FADH 2, being oxidized in CPE, provides the synthesis of 2 ATP molecules;
2. Enoyl-CoA hydratase adds water to the double bond of Enoyl-CoA to form β-hydroxyacyl-CoA;
3. β-hydroxyacyl-CoA is oxidized by NAD dependent dehydrogenase to β-ketoacyl-CoA. Reduced NADH 2, being oxidized to CPE, ensures the synthesis of 3 ATP molecules;
4. Thiolase with the participation of HCoA cleaves Acetyl-CoA from β-ketoacyl-CoA. As a result of 4 reactions, Acyl-CoA is formed, which is shorter than the previous Acyl-CoA by 2 carbons. Formed Acetyl-CoA, being oxidized in the TCA, provides the synthesis of 12 ATP molecules in the CPE.
Then Acyl-CoA again enters into β-oxidation reactions. Cycles continue until Acyl-CoA is converted to Acetyl-CoA with 2 C atoms (if the FA had an even number of C atoms) or Butyryl-CoA with 3 C atoms (if the FA had an odd number of C atoms).
FA oxidation in peroxisomes
In peroxisomes, FA oxidation proceeds in a modified form. This pathway provides catabolism in the liver of long-chain fatty acids (C=20, 22). The oxidation products are actonoyl-CoA, Acetyl-CoA and H 2 O 2 . H 2 O 2 is synthesized by aerobic dehydrogenase during the interaction of FADH 2 and O 2. Actonoil and Acetyl pass from CoA to carnitine and are sent to the mitochondria, where they are oxidized to form ATP.
α-oxidation of fatty acids
α-oxidation- a specific catabolism pathway for fatty acids with a long (more than 20 carbon atoms) and branched hydrocarbon chain. α-oxidation occurs in the nervous tissue, where long-chain fatty acids predominate, and in the liver, where branched fatty acids of plant foods (for example, phytanic acid) enter.
During α-oxidation, ATP synthesis does not occur, one C atom is split off from the FA, in the form of CO 2.
Phytanic acid, a branched hydrocarbon fatty acid, is formed from phytol, which is part of chlorophyll. In this acid, every third C atom has a methyl group, which makes the β-oxidation of this acid impossible. In the α-oxidation of phytanic acid, the methyl group is first removed, and then the β-oxidation cycle occurs.
ω-Oxidation of LC
I approve
Head cafe prof., d.m.s.
Meshchaninov V.N.
______''_____________2005
Lecture No. 12 Topic: Digestion and absorption of lipids. Transport of lipids in the body. Lipoprotein exchange. Dyslipoproteinemia.
Faculties: medical and preventive, medical and preventive, pediatric.
Lipids - this is a group of organic substances diverse in structure, which are united by a common property - solubility in non-polar solvents.
Lipid classification
According to their ability to hydrolyze in an alkaline environment with the formation of soaps, lipids are divided into saponifiable (contain fatty acids) and unsaponifiable (single-component).
Saponifiable lipids contain in their composition mainly alcohols glycerol (glycerolipids) or sphingosine (sphingolipids), according to the number of components they are divided into simple (consist of 2 classes of compounds) and complex (consist of 3 or more classes).
Simple lipids include:
1) wax (ester of higher monohydric alcohol and fatty acid);
2) triacylglycerides, diacylglycerides, monoacylglycerides (an ester of glycerol and fatty acids). In a person weighing 70 kg, TG is about 10 kg.
3) ceramides (ester of sphingosine and C18-26 fatty acid) - are the basis of sphingolipids;
Complex lipids include:
1) phospholipids (contain phosphoric acid):
a) phospholipids (ester of glycerol and 2 fatty acids, contains phosphoric acid and amino alcohol) - phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol;
b) cardiolipins (2 phosphatidic acids connected through glycerol);
c) plasmalogens (an ester of glycerol and a fatty acid, contains an unsaturated monohydric higher alcohol, phosphoric acid and amino alcohol) - phosphatidalethanolamines, phosphatidalserins, phosphatidalcholines;
d) sphingomyelins (ester of sphingosine and C18-26 fatty acid, contains phosphoric acid and amino alcohol - choline);
2) glycolipids (contain carbohydrate):
a) cerebrosides (ester of sphingosine and C18-26 fatty acid, contains hexose: glucose or galactose);
b) sulfatides (an ester of sphingosine and C18-26 fatty acid, contains hexose (glucose or galactose) to which sulfuric acid is attached in the 3 position). Many in white matter;
c) gangliosides (ester of sphingosine and C18-26 fatty acid, contains oligosaccharide from hexoses and sialic acids). Found in ganglion cells
Unsaponifiable lipids include steroids, fatty acids (a structural component of saponifiable lipids), vitamins A, D, E, K, and terpenes (hydrocarbons, alcohols, aldehydes, and ketones with several isoprene units).
Biological functions of lipids
Lipids perform a variety of functions in the body:
Structural. Complex lipids and cholesterol are amphiphilic, they form all cell membranes; phospholipids line the surface of the alveoli, form a shell of lipoproteins. Sphingomyelins, plasmalogens, glycolipids form myelin sheaths and other membranes of nerve tissues.
Energy. In the body, up to 33% of all ATP energy is formed due to lipid oxidation;
Antioxidant. Vitamins A, D, E, K prevent FRO;
Reserve. Triacylglycerides are the storage form of fatty acids;
Protective. Triacylglycerides, as part of adipose tissue, provide thermal insulation and mechanical protection of tissues. Waxes form a protective lubricant on human skin;
Regulatory. Phosphotidylinositols are intracellular mediators in the action of hormones (inositol triphosphate system). Eicosanoids are formed from polyunsaturated fatty acids (leukotrienes, thromboxanes, prostaglandins), substances that regulate immunogenesis, hemostasis, nonspecific resistance of the body, inflammatory, allergic, proliferative reactions. Steroid hormones are formed from cholesterol: sex and corticoids;
Vitamin D and bile acids are synthesized from cholesterol;
digestive. Bile acids, phospholipids, cholesterol provide emulsification and absorption of lipids;
Informational. Gangliosides provide intercellular contacts.
The source of lipids in the body are synthetic processes and food. Some lipids are not synthesized in the body (polyunsaturated fatty acids - vitamin F, vitamins A, D, E, K), they are indispensable and come only with food.
Principles of lipid regulation in nutrition
A person needs to eat 80-100 g of lipids per day, of which 25-30 g of vegetable oil, 30-50 g of butter and 20-30 g of animal fat. Vegetable oils contain a lot of polyene essential (linoleic up to 60%, linolenic) fatty acids, phospholipids (removed during refining). Butter contains many vitamins A, D, E. Dietary lipids contain mainly triglycerides (90%). About 1 g of phospholipids and 0.3-0.5 g of cholesterol enter with food per day, mainly in the form of esters.
The need for dietary lipids depends on age. For infants, lipids are the main source of energy, and for adults, glucose. Newborns 1 to 2 weeks old require lipids 1.5 g / kg, children - 1 g / kg, adults - 0.8 g / kg, the elderly - 0.5 g / kg. The need for lipids increases in the cold, during physical exertion, during convalescence and during pregnancy.
All natural lipids are well digested, oils are absorbed better than fats. With a mixed diet, butter is absorbed by 93-98%, pork fat - by 96-98%, beef fat - by 80-94%, sunflower oil - by 86-90%. Prolonged heat treatment (> 30 min) destroys useful lipids, while forming toxic fatty acid oxidation products and carcinogens.
With insufficient intake of lipids from food, immunity decreases, the production of steroid hormones decreases, and sexual function is impaired. With a deficiency of linoleic acid, vascular thrombosis develops and the risk of cancer increases. With an excess of lipids in the diet, atherosclerosis develops and the risk of breast and colon cancer increases.
Digestion and absorption of lipids
digestion it is the hydrolysis of nutrients to their assimilated forms.
Only 40-50% of dietary lipids are completely broken down, and from 3% to 10% of dietary lipids can be absorbed unchanged.
Since lipids are insoluble in water, their digestion and absorption has its own characteristics and proceeds in several stages:
1) Lipids of solid food under mechanical action and under the influence of bile surfactants are mixed with digestive juices to form an emulsion (oil in water). The formation of an emulsion is necessary to increase the area of action of enzymes, because. they only work in the aqueous phase. Liquid food lipids (milk, broth, etc.) enter the body immediately in the form of an emulsion;
2) Under the action of lipases of digestive juices, the lipids of the emulsion are hydrolyzed with the formation of water-soluble substances and simpler lipids;
3) Water-soluble substances isolated from the emulsion are absorbed and enter the blood. The simpler lipids isolated from the emulsion combine with bile components to form micelles;
4) Micelles ensure the absorption of lipids into intestinal endothelial cells.
Oral cavity
In the oral cavity, mechanical grinding of solid food and wetting it with saliva (pH=6.8) takes place. Here begins the hydrolysis of triglycerides with short and medium fatty acids, which come with liquid food in the form of an emulsion. Hydrolysis is carried out by lingual triglyceride lipase (“tongue lipase”, TGL), which is secreted by the Ebner glands located on the dorsal surface of the tongue.
Stomach
Since "tongue lipase" acts in the pH range of 2-7.5, it can function in the stomach for 1-2 hours, breaking down up to 30% of triglycerides with short fatty acids. In infants and young children, it actively hydrolyzes milk TG, which contain mainly fatty acids with short and medium chain length (4-12 C). In adults, the contribution of tongue lipase to TG digestion is negligible.
Produced in the chief cells of the stomach gastric lipase , which is active at neutral pH, characteristic of the gastric juice of infants and young children, and is not active in adults (pH of gastric juice ~ 1.5). This lipase hydrolyzes TG, mainly cleaving off fatty acids at the third carbon atom of glycerol. FAs and MGs formed in the stomach are further involved in the emulsification of lipids in the duodenum.
Small intestine
The main process of lipid digestion occurs in the small intestine.
1. Emulsification lipids (mixing of lipids with water) occurs in the small intestine under the action of bile. Bile is synthesized in the liver, concentrated in the gallbladder and, after eating fatty foods, is released into the lumen of the duodenum (500-1500 ml / day).
Bile it is a viscous yellow-green liquid, has pH = 7.3-8.0, contains H 2 O - 87-97%, organic substances (bile acids - 310 mmol / l (10.3-91.4 g / l), fatty acids - 1.4-3.2 g / l, bile pigments - 3.2 mmol / l (5.3-9.8 g / l), cholesterol - 25 mmol / l (0.6-2.6) g / l, phospholipids - 8 mmol / l) and mineral components (sodium 130-145 mmol / l, chlorine 75-100 mmol / l, HCO 3 - 10-28 mmol / l, potassium 5-9 mmol / l). Violation of the ratio of bile components leads to the formation of stones.
bile acids (cholanic acid derivatives) are synthesized in the liver from cholesterol (cholic and chenodeoxycholic acids) and formed in the intestine (deoxycholic, lithocholic, etc. about 20) from cholic and chenodeoxycholic acids under the action of microorganisms.
In bile, bile acids are present mainly in the form of conjugates with glycine (66-80%) and taurine (20-34%), forming paired bile acids: taurocholic, glycocholic, etc.
Bile salts, soaps, phospholipids, proteins and the alkaline environment of bile act as detergents (surfactants), they reduce the surface tension of lipid droplets, as a result, large droplets break up into many small ones, i.e. emulsification takes place. Emulsification is also facilitated by intestinal peristalsis and released, during the interaction of chyme and bicarbonates, CO 2: H + + HCO 3 - → H 2 CO 3 → H 2 O + CO 2.
2. Hydrolysis triglycerides carried out by pancreatic lipase. Its pH optimum is 8, it hydrolyzes TG predominantly in positions 1 and 3, with the formation of 2 free fatty acids and 2-monoacylglycerol (2-MG). 2-MG is a good emulsifier. 28% of 2-MG is converted into 1-MG by isomerase. Most of the 1-MG is hydrolyzed by pancreatic lipase to glycerol and a fatty acid.
In the pancreas, pancreatic lipase is synthesized together with the protein colipase. Colipase is formed in an inactive form and is activated in the intestine by trypsin by partial proteolysis. Colipase, with its hydrophobic domain, binds to the surface of the lipid droplet, while its hydrophilic domain promotes the maximum approach of the active center of pancreatic lipase to TG, which accelerates their hydrolysis.
3. Hydrolysis lecithin occurs with the participation of phospholipases (PL): A 1, A 2, C, D and lysophospholipase (lysoPL).
As a result of the action of these four enzymes, phospholipids are cleaved to free fatty acids, glycerol, phosphoric acid and an amino alcohol or its analogue, for example, the amino acid serine, however, part of the phospholipids is cleaved with the participation of phospholipase A2 only to lysophospholipids and in this form can enter the intestinal wall.
PL A 2 is activated by partial proteolysis with the participation of trypsin and hydrolyzes lecithin to lysolecithin. Lysolecithin is a good emulsifier. LysoFL hydrolyzes part of lysolecithin to glycerophosphocholine. The remaining phospholipids are not hydrolyzed.
4. Hydrolysis cholesterol esters to cholesterol and fatty acids is carried out by cholesterol esterase, an enzyme of the pancreas and intestinal juice.
Since lipids are basically hydrophobic molecules, they are transported in the aqueous phase of the blood as part of special particles - lipoproteins.
The structure of transport lipoproteins can be compared to walnut who have shell And core. The "shell" of the lipoprotein is hydrophilic, the core is hydrophobic.
- the surface hydrophilic layer is formed phospholipids(their polar part), cholesterol(its OH group), squirrels. The hydrophilicity of the lipids of the surface layer is designed to ensure the solubility of the lipoprotein particle in the blood plasma,
- "core" form non-polar cholesterol esters(XC) and triacylglycerols(TAG), which are transportable fats. Their ratio fluctuates in different types of lipoproteins. The fatty acid residues of phospholipids and the cyclic part of cholesterol also face the center.
Scheme of the structure of any transport lipoprotein
There are four main classes of lipoproteins:
- lipoproteins high density(HDL, α-lipoproteins, α-LP),
- low density lipoproteins (LDL, β-lipoproteins, β-LP),
- very low density lipoproteins (VLDL, pre-β-lipoproteins, pre-β-LP),
- chylomicrons (XM).
The properties and functions of lipoproteins of different classes depend on their composition, i.e. on the type of proteins present and on the ratio of triacylglycerols, cholesterol and its esters, phospholipids.
Comparison of the size and properties of lipoproteins
Functions of lipoproteins
The functions of blood lipoproteins are
1. Transfer to cells of tissues and organs
- saturated and monounsaturated fatty acids in the composition of triacylglycerols for subsequent deposition or use as energy substrates,
- polyunsaturated fatty acids in the composition of cholesterol esters for use by cells in the synthesis of phospholipids or the formation of eicosanoids,
- cholesterol as a membrane material,
- phospholipids as membrane material,
Chylomicrons and VLDL are primarily responsible for transport fatty acids within TAG. High and low density lipoproteins - for the transport of free cholesterol And fatty acids in its broadcasts. HDL is also able to give cells part of its phospholipid membrane.
2. Removal of excess cholesterol from cell membranes.
3. Transport of fat-soluble vitamins.
4. Transfer of steroid hormones (along with specific transport proteins).
Lipoprotein apoproteins
The proteins in lipoproteins are commonly referred to as apoproteins, there are several types of them - A, B, C, D, E. In each class of lipoproteins there are corresponding apoproteins that perform their own function:
1. Structural function(" stationary"proteins) - bind lipids and form protein-lipid complexes:
- apoB-48- attaches triacillicerols,
- apoB-100- binds both triacylglycerols and cholesterol esters,
- apoA-I- accepts phospholipids
- apoA-IV- binds to cholesterol.
2. Cofactor function(" dynamic"proteins) - affect the activity of enzymes of the metabolism of lipoproteins in the blood.
FEDERAL STATE EDUCATIONAL INSTITUTION OF HIGHER PROFESSIONAL EDUCATION "MOSCOW STATE ACADEMY OF VETERINARY MEDICINE AND BIOTECHNOLOGY named after K. I. SKRYABIN"
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LIPID METABOLISM AND ITS DISTURBANCES IN THE ANIMAL BODY
lecture
Recommended by the educational and methodological commission of the faculty of veterinary medicine of the MGAVMiB. for students studying in the specialty 111201 - Veterinary
Moscow 2009
UDC 636: 612.015
Associate Professor of the Department of Pathological Physiology. V. M. Koropova, Candidate of Biological Sciences Lipid metabolism and its disorders in animals: Lecture. – M.: FGOU VPO MGAVMiB, 2009, 19 p.
Material is presented on the main mechanisms of lipid metabolism in animals and some of their disorders.
Intended for students of the Faculty of Veterinary Medicine.
Reviewers: , doctor of biological sciences, professor; , doctor of biological sciences, professor.
Approved by the educational and methodological commission of the Faculty of Veterinary Medicine (minutes dated April 9, 2009).
Abbreviations used………………………..………………4
1. The value of lipids in the body………………………….………. five
2. Digestion and absorption of lipids, their disorders …………6
3. Transport of lipids in the body……… ………………………………………………7
4. Hyperlipemia………………………………………………… …..9
5. Neurohumoral regulation of lipostat ………………………..9
6. Violations of the lipostat…………………………………………….11
7. Ketosis and steatosis of the liver………………………………………….12
8. Role of lipid peroxidation in cell damage...15
9. Eicosanoids………………………………………………………… 16
10. Atherosclerosis………………………………………………………… 17
Bibliographic list……………………………………………18
Abbreviations used.
ACoA - acetyl coenzyme A
BAS - biologically active substances
SMC - smooth muscle cells
VFA - volatile fatty acids
LP - lipoproteins
LPL - lipoprotein lipase
LDL - low density lipoproteins
VLDL - very low density lipoproteins
LDLP - Intermediate Density Lipoproteins
LPO - lipid peroxidation
FFA - free fatty acids
TAG - triacylglycerides (fats)
FLIP - phospholipids
XM - chylomicrons
CN - cholesterol
TCA cycle of tricarboxylic acids
EC - cholesterol esters
Lipids- a group of hydrophobic substances soluble in organic solvents (ether, benzene, acetone), built with the participation of alcohols and fatty acids.
1, The importance of lipids in the body
TO simple lipids include fatty acids and acylglycerides (for example, neutral fats - triacylglycerides), steroids (cholesterol and its esters with fatty acids, bile acids, calciferols), waxes (lanolin, spermaceti).
Complex lipids in addition to alcohols and fatty acids, they have residues of compounds of other classes - phosphoric acid, nitrogenous bases, carbohydrates. Complex lipids include phospholipids, sphingolipids, etc.
Triacylglycerides (TAGs) are mainly located in the subcutaneous adipose tissue, performing reserve-energy, heat-insulating and shock-absorbing functions. An important depreciation role is also played by the fat pad around the kidneys, heart, and eyeball. During the oxidation of TAG, not only the most a large number of energy, but also water, which is important for obtaining endogenous moisture for animals in arid places and deserts (camels, gerbils, etc.). For energy needs, skeletal muscles partially, and the myocardium mainly uses fatty acids, the brain - glucose, but is also able to utilize ketone bodies.
Phospholipids and cholesterol perform a membrane-forming function. Cholesterol derivatives - steroid hormones of the adrenal cortex and gonads - perform regulatory functions. Nervous tissue lipids contain up to 50% dry matter, mainly phospholipids (FLIP) and sphingolipids.
Alimentary lipid deficiency is dangerous primarily due to the absence of polyunsaturated fatty acids. In the human body, linoleic and linolenic acids are not synthesized, so they were called irreplaceable, or essential. Together with other polyenoic acids, they were designated as vitamin F (from the English fat - fat), although the need for them is several grams per day, and they do not fall under the criteria for true vitamins. In experiments on rats with vitamin F deficiency, growth retardation, dermatitis, and alopecia with hyperkeratosis phenomena were recorded. Fat-soluble vitamins A, D, E, K are supplied with lipids in the body. With a lack of the latter, there are violations of growth, development, reproductive function, reduced resistance, etc. It should be noted that ruminants will not experience a deficiency of polyunsaturated fatty acids, which is associated with feeding habits and digestion. Plant foods contain a lot of unsaturated acids.
2. Digestion and absorption of lipids, their disorders
Lipid digestion occurs in the small intestine. Since lipids are insoluble in water, the action of lipolytic enzymes is preceded by emulsification of lipids with bile salts (taurocholic, glycocholic). As a result, large lipid droplets are dispersed into many small ones, increasing the area of influence for pancreatic enzymes - lipase, phospholipase A, cholesterol esterase). Since milk is the only natural product containing emulsified fats, the breakdown of its components in young mammals begins already in the stomach under the action of gastric lipase, which is active at a neutral pH value (in adults it is inactive, because the pH of their gastric juice is 1.5 - 2.5). In the future, the breakdown of milk fats continues in the intestine under the action of pancreatic lipase. The products of lipid hydrolysis are fatty acids, 2-monoacylglycerides, cholesterol, etc. They form mixed micelles with bile acids, phospholipids and bile cholesterol, which diffuse through the membranes into enterocytes. Fat-soluble vitamins are also absorbed along with them.
in mucosal cells small intestine there is a resynthesis of fats, already characteristic of this organism, as well as cholesterol esters and FLIP. These components and proteins form lipoprotein complexes - chylomicrons (XM). They are large in size, therefore, by exocytosis, they are first released into the chyle, which is formed in the lymphatic system of the intestinal villi, and through the thoracic lymphatic duct enter the systemic circulation. Some of them are then deposited by the lungs.
Short fatty acids (up to 10 carbon atoms, for example, acetic, propionic, butyric) are absorbed without micelles, directly into the portal vein, bind to transport albumin and are transferred to the liver.
The causes of impaired digestion and absorption of lipids can be various factors.
2. Violation of the secretion of pancreatic juice with lipolytic enzymes.
3. Diarrhea and acceleration of intestinal motility
4. Damage to the intestinal epithelium by various poisons (monioiodoacetate, salts of heavy metals), infectious agents, antibiotics (neomycin).
5. Violation of the nervous and endocrine regulation - a decrease in the activity of the vagus, an excess of adrenaline, a lack of the hormone of the adrenal cortex, thyroxine weaken the absorption of fats. This also leads to a deficiency of cholecystokinin and gastrin - hormones of the gastrointestinal tract that regulate the contraction of the gallbladder, the processes of emulsification and breakdown of fats.
6. Excess in food and water of divalent alkaline earth cations (calcium, magnesium), which leads to the formation of insoluble salts of fatty acids.
In all cases of impaired digestion and absorption of lipids, they appear in large quantities in the feces. This is called steatorrhea. If steatorrhea is caused by acholia, then the stool, in addition to being clayey in appearance, also becomes whitish, discolored due to the absence of bile pigments. At the same time, due to the loss of fat-soluble vitamins and polyene fatty acids, hair loss, hair loss, dermatitis, bleeding, and osteoporosis may occur. In advanced cases, exhaustion of the body develops.
3. Transport of lipids in the body
The formation of lipoproteins (LP) in the body is a necessity due to the hydrophobicity (insolubility) of lipids. The latter are dressed in a protein shell formed by special transport proteins - apoproteins, which ensure the solubility of lipoproteins. In addition to chylomicrons (HM), very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) are formed in the body of animals and humans. A fine division into classes is achieved by ultracentrifugation in a density gradient and depends on the ratio of the amount of proteins and lipids in the particles, since lipoproteins are supramolecular formations based on non-covalent bonds. At the same time, HMs are located on the surface of the blood serum due to the fact that they contain up to 85% fat, and it is lighter than water, at the bottom of the centrifuge tube there are HDL containing the largest amount of proteins.
Another classification of LP is based on electrophoretic mobility. During electrophoresis in polyacrylamide gel XM as the largest particles remain at the start, VLDL form pre-β - LP fraction, LDL and CDL - β - LP fraction, HDL - α - LP fraction.
All drugs are built from a hydrophobic core (fats, cholesterol esters) and a hydrophilic shell, represented by proteins, as well as phospholipids and cholesterol. Their hydrophilic groups face the aqueous phase, while the hydrophobic parts face the center, the core. Each type of LP is formed in different tissues and transports certain lipids. So, XM transports fats obtained from food from the intestines to the tissues. HM is 84-96% composed of exogenous triacylglycerides. In response to the fat load, capillary endotheliocytes release the enzyme lipoprotein lipase (LPL) into the blood, which hydrolyzes the XM fat molecules to glycerol and fatty acids. Fatty acids enter various tissues, and soluble glycerol is transported to the liver, where it can be used for fat synthesis. LPL is most active in the capillaries of adipose tissue, heart and lungs, which is associated with the active deposition of fat in adipocytes and the peculiarity of metabolism in the myocardium, which uses a lot of fatty acids for energy purposes. In the lungs, fatty acids are used to synthesize surfactant and ensure the activity of macrophages. It is no accident that badger and bear fat are used in folk medicine for pulmonary pathologies, and northern peoples living in harsh climatic conditions rarely get sick with bronchitis and pneumonia, consuming fatty foods.
On the other hand, high LPL activity in adipose tissue capillaries contributes to obesity. There is also evidence that during starvation it decreases, but the activity of muscle LPL increases.
Residual HM particles are captured by endocytosis by hepatocytes, where they are cleaved by lysosome enzymes to amino acids, fatty acids, glycerol, and cholesterol. One part of cholesterol and other lipids is directly excreted into bile, another part is converted into bile acids, and the third part is included in VLDL. The latter contain 50-60% of endogenous triacylglycerides, therefore, after their secretion into the blood, they are subjected, like HM, to the action of lipoprotein lipase. As a result, VLDL lose TAGs, which are then used by cells of adipose and muscle tissues. In the course of catabolism of VLDL, the relative percentage of cholesterol and its esters (EF) increases (especially with the consumption of food rich in cholesterol), and VLDL is converted into LDLP, which in many mammals, especially rodents, are taken up by the liver and completely cleaved in hepatocytes. In humans, primates, birds, pigs, a large part of LDL in the blood that is not captured by hepatocytes is converted into LDL. This fraction is richest in cholesterol and HM, and since high level cholesterol is one of the first risk factors for the development of atherosclerosis, then LDL is called the most atherogenic fraction of LP. LDL cholesterol is used by the adrenal glands and gonads to synthesize steroid hormones. LDL supply cholesterol to hepatocytes, renal epithelium, lymphocytes, cells of the vascular wall. Due to the fact that the cells themselves are able to synthesize cholesterol from acetylcoenzyme A (AcoA), there are physiological mechanisms that protect the tissue from an excess of CM: inhibition of the production of its own internal cholesterol and receptors for LP apoproteins, since any endocytosis is receptor-mediated. HDL drainage system is recognized as the main stabilizer of cellular cholesterol.
HDL precursors are formed in the liver and intestines. They contain a high percentage of proteins and phospholipids, are very small in size, freely penetrate through the vascular wall, binding excess ChM and removing it from the tissues, and themselves become mature HDL. Part of the EC passes directly in the plasma from HDL to VLDL and LPPP. Eventually, all LPs are cleaved by lysosomes of hepatocytes. Thus, almost all the "extra" cholesterol enters the liver and is excreted from it as part of bile into the intestine, being removed with feces.
4. Hyperlipemia
Hyperlipemia is an increase in blood fat. Hyperlipemia can be alimentary, transport and retention.
Alimentary hyperlipemia occurs after ingestion of fatty foods. Simultaneously with an increase in the content of fat in the blood, an increase in the content of other substances from the lipid group (phospholipids, cholesterol) can be observed. The total increase in these substances is called lipidemia. Alimentary hyperlipemia is most often characterized by a temporary increase in chylomicrons in the blood.
Transport hyperlipemia is associated with an increase in the breakdown of fats and the release of free fatty acids (FFA) from the depot during starvation, stress, and diabetes mellitus. Lipolysis of adipose tissue, bone marrow is promoted by adrenaline, glucagon, thyroxine, somatotropin and adrenocorticotropic hormone. The mobilization of fat from the lungs, leading to hyperlipemia, occurs with prolonged hyperventilation of the lungs (this partly explains the obesity of many opera singers).
retention hyperlipemia (from lat. retentio - delay) develops due to a delay in the transfer of neutral fats from the blood to the tissues. It may be due to an insufficient concentration of albumins that transport FFA - with liver pathology (insufficient albumin synthesis), with nephrotic syndrome (protein loss in the urine).
Retention hyperlipemia may be associated with insufficient activity of lipoprotein lipase: due to a decrease in heparin, which activates it in atherosclerosis, nephrosis; due to a lack of lipocaine, which activates the flow of LPL into the blood, in diabetes mellitus.
5. Neurohumoral regulation of lipostat
Lipostat is conventionally called a system that controls the constancy of the body weight of an adult organism. The central regulatory link of the lipostat is the hypothalamus, where the nuclei of the autonomic nervous system. In 1961, an Indian pathophysiologist established that the hunger center is located in the ventro-lateral nuclei of the hypothalamus, and the saturation (satiety) center is located in the ventro-medial nuclei. The satiety center is connected to the hunger center by synapses that transmit inhibitory impulses. processes in the body lipogenesis(fat formation) and lipolysis, or fat mobilization (i.e., splitting it into glycerol and fatty acids) are active and constant, and most of all they are expressed in adipose tissue.
Adipose tissue is not an inert, as it seems at first glance, but a metabolically very active formation, with constantly ongoing processes of synthesis and breakdown of fats, proteins, carbohydrates. Adipocytes - cells of adipose tissue - are formed from fibroblasts. Adipocytes have many neurotransmitter and hormonal receptors on their surface (remember, for example, that adipose tissue is insulin-dependent).
In the "satiated" state, adipocytes secrete the peptide hormone leptin, which binds to the leptin receptors of the ventromedial nuclei (satiation center). From the center of saturation, inhibitory signals are sent to the center of hunger, and hunger recedes. Also, under the influence of leptin, the production of neuropeptide Y decreases in the center of hunger. Neuropeptide Y stimulates feeding behavior, the search for and consumption of food by animals, and insulin production. Thus, initially the fat cell itself normally responds to saturation and sends leptin signals about it.
Lipogenesis activated after eating. In the blood, the concentration of glucose rises, which stimulates the secretion of insulin. Under the action of insulin, glucose transporter proteins (GLUT-4) are activated, and it enters adipocytes, where it is converted into glycerophosphate. Insulin also activates the synthesis of lipoprotein lipase by adipocytes and its exposure to the walls of the capillary surface. LPL hydrolyzes chylomicron fats and VLDL to glycerol and fatty acids. Glycerol is transported to the liver, since there are no enzymes for it in adipocytes, and fatty acids penetrate into them, bind to the formed glycerophosphate and turn into their own triacylglycerides. Thus, if there is a significant amount of glucose in food, excessive deposition of fat in adipose tissue is possible, since activated glycerol is formed there only from glucose.
The liver also increases the synthesis of fats and their secretion into the blood as part of VLDL. VLDL deliver fats to the capillaries of adipose and muscle tissue, where they undergo hydrolysis by LPL.
In the intervals between meals, during fasting, the concentration of insulin in the blood decreases, but the content of glucagon increases. During physical activity, the secretion of adrenaline increases. An increase in sympathoadrenal activity, glucagon levels contributes to an increase lipolysis. Fatty acids released into the blood bind to albumin and become an important source of energy for the muscles, heart, liver and kidneys. However, the absolute concentration of FFAs is not high even in this time interval, since the half-life of fatty acids is very short (less than 5 minutes), they are rapidly metabolized, carrying a large flow of energy. Lipolysis stops after eating and insulin secretion.
Glucocorticoid hormones enhance the mobilization of fat from adipose tissue. But this action may be overshadowed by other effects of these hormones: the ability to induce hyperglycemia through gluconeogenesis and stimulate insulin secretion. And insulin, as already mentioned, stimulates lipogenesis.
Involvement of the nervous system in the regulation fat metabolism This is confirmed by the data that prolonged emotional stress leads to the mobilization of fat from fat depots and weight loss. The same effect is observed when the sympathetic nerves are stimulated. Desympathization prevents the release of fat from the depot. Irritation of the parasympathetic nerves is accompanied by the deposition of fat.
6. Lipostat disorder
Violation of the complex system of neurohumoral regulation underlies the excessive deposition of fat in adipose tissue - obesity.
_Primary obesity develops with an increased caloric content of the diet, exceeding the energy needs of the body. Recently, it is believed that absolute or relative leptin deficiency plays a key role in the development of primary obesity.
Humans and animals have an obese gene (ob) that codes for leptin. As a result of a gene mutation, the amount of leptin in the blood decreases (absolute leptin deficiency). Low level leptin in the blood serves as a signal of an insufficient amount of fat in the body. The hunger center continues the secretion of neuropeptide Y, leading to an increase in appetite and, as a result, an increase in body weight.
In other cases, there may be a genetic defect in leptin receptors in the hypothalamus. At the same time, the amount of leptin increases several times, but its relative lack of action on the hypothalamus keeps the hunger center in constant activity.
It is worth emphasizing that obesity is a matter of balance. Overweight gain is impossible without excess energy intake over its costs, therefore physical inactivity is a risk factor for the development of obesity.
Secondary obesity manifests itself as a syndrome in the development of primary neuroendocrine disorders, leading to an imbalance between lipogenesis and lipolysis. Thus, hypothyroidism, hypercorticosolism, hyperinsulinism, and some brain tumors lead to the development of obesity.
Obese cows are more likely than average fat cows to develop ketosis. In obese animals, the sexual cycle is disturbed, cows often remain infertile. Calves, lambs, piglets, puppies from obese mothers are often born weak, prone to disease. With obesity, the functioning of the musculoskeletal system is disrupted, the load on the heart increases, fatigue appears, and the risk of developing atherosclerosis and thrombosis increases.
In contrast to obesity, there may be exhaustion characterized by a significant loss of body fat reserves. Exhaustion is observed with prolonged fasting, severe hyperpyretic fevers, type 1 diabetes mellitus, and emotional stress.
The lipolytic effect is strongly pronounced in hyperthyroidism, with an increased release of adrenaline and norepinephrine by the adrenal medulla, chronic diseases. Cancerous cachexia, which occurs due to intoxication, is well known. In addition, malignant cells are "traps" for glucose and other energy equivalents. In type 1 diabetes mellitus (hypoinsulinemia), the anabolic effects of insulin on lipids and proteins drop out. Therefore, exhaustion is a mandatory part clinical picture insulin dependent diabetes. Cachexia is manifested in severe long-term lesions of the gastrointestinal tract associated with impaired absorption of substances.
7. Ketosis and hepatic steatosis
The central link of all exchanges is acetylcoenzyme A. It is formed during the breakdown of glucose, glycerol, some amino acids, and β-oxidation of fatty acids. The main amount of ACoA is then oxidized in the tricarboxylic acid cycle to water and carbon dioxide, providing energy production. Sufficient amounts of oxaloacetate are required to involve ACoA in the TCA cycle. The other part of ACoA serves as the basis for the synthesis of fatty acids, the third - cholesterol, the fourth is used for the formation of ketone bodies. Ketone bodies are water-soluble molecules - acetone, acetoacetic and β - hydroxybutyric acids. In monogastric animals and humans, the synthesis of ketone bodies occurs only in the mitochondria of the liver. In monogastric animals, they can form even in the mucous membrane of the proventriculus.
Ketone bodies can be used for energy needs by the brain, muscles, kidneys and lungs, especially in fasting conditions. During pregnancy, they are utilized by the placenta and fetus. Ketone bodies are normal metabolites that are rapidly utilized, so their blood concentrations are low (3-10 mg/dl in humans, up to 6 ml/dl in cattle and small animals).
During prolonged fasting, ketone bodies become the main source of energy for skeletal muscles, the heart, and kidneys, while glucose is consumed by the brain and red blood cells. Then the brain adapts to the use of acetoacetic acid. If ketone bodies accumulate in the blood in excess (ketonemia), then they appear in the urine (ketonuria), and in lactating animals and in milk (ketonolactia), the milk becomes bitter, unsuitable for use. This state is called ketosis. With sweat, urine, milk, as a rule, acetone is removed, which is not utilized by the tissues. It is acetone that creates a peculiar fruity smell of an animal or a person.
Hyperketonemia is dangerous for the body, as it leads to acidosis, first compensated, with a decrease in alkaline reserve, and then to uncompensated, with a shift in pH. The accumulation of protons in the blood disrupts the binding of oxygen by hemoglobin and the function of other proteins, including enzymatic ones. There are other metabolic disorders, signs of cardiovascular insufficiency. In animals, appetite decreases or is perverted, weight is lost, productivity decreases, and abortions often occur. With acidosis, the bones lose calcium, the first signs of this are the resorption of the caudal vertebrae and the last ribs, the fragility of the horns. Hyperketonemia can lead to ketoacidotic coma.
The main link in the pathogenesis of ketosis is the accelerated breakdown of fats with the formation of ACoA against the background of a deficiency of carbohydrates or oxaloacetate for TCA.
Conditionally distinguish between primary and secondary ketosis. Primary ketosis occurs in ruminants as a result of unbalanced or poor-quality feeding. Most often, primary ketosis affects highly productive cows during the period of highest lactation or before calving, obese, with multiple pregnancies of sheep and goats. Unproductive cattle, pigs, horses are resistant to the development of ketosis.
Carbohydrate starvation can occur when the sugar-protein ratio in the diet decreases from the optimal 1-1.5:1 to 0.2-0.6:1. When giving concentrated feeds rich in protein, cake and other high-fat components, the digestion of cellulose by the rumen microflora is inhibited, the proportion of volatile fatty acids (VFA) changes: butyric acid (ketogenic) accumulates to the detriment of propionic (anti-ketogenic). Glucose is synthesized from it by gluconeogenesis. Do not feed silage with a high content of butyric acid, rotten and moldy feed. They inhibit lactic acid fermentation - a source of VFAs and, ultimately, glucose. This is how carbohydrate deficiency occurs. In highly productive lactating cows, it is exacerbated by the secretion of carbohydrates with milk: it is estimated that a cow secretes up to 2 kg of milk sugar per lactation!
In conditions of intense metabolism, the animal requires large supplies of energy. Therefore, the mobilization of fat from the depot, β-oxidation of fatty acids and the formation of ACoA are enhanced. "Fats burn in the flame of carbohydrates." How to understand this famous phrase? In order for ACoA to be oxidized into TCA, it must bind to oxaloacetate (oxalic acid), which itself is synthesized from pyruvic acid, a breakdown product of glucose. With a lack of glucose, there is a deficiency of oxaloacetate and the inability to include all ACoA in the TCA. Excess ACoA is used to synthesize ketone bodies, a bypass energy supplier.
Knowledge of the pathogenesis of ruminant ketosis allows the use of propionic acid and glucose as therapeutic and corrective drugs.
Secondary ketosis occurs in animals and humans due to a primary disease of any organs. Secondary ketosis can be with general starvation, diabetes mellitus, debilitating fever, heavy muscle load, liver pathologies.
Ketoacidosis reaches dangerous levels in diabetes mellitus, the concentration of ketone bodies in this disease can reach up to 400-500 mg / dl. Ketoacidotic coma is one of the causes of death in diabetes mellitus.
Common in the pathogenesis of ketosis of any etiology is the depletion of carbohydrate reserves and increased lipolysis. A large flow of lipid material in the form of FFA associated with albumin rushes to the liver. The liver metabolizes the rests of HM, LDL, HDL and secretes VLDL and HDL precursors. If the intake of lipids in the liver prevails over the rate of assembly and secretion of VLDL, then a long-term retention of fats leads to steatosis, fatty liver (fatty hepatosis). The fat content in the liver then exceeds 8-10% by weight of dry matter. The same phenomena can be observed in other organs. Increased for a long time fat content in tissues (with the exception of fat) is called fatty infiltration. Violation of the relationship between fat and protein leads to the accumulation of smaller or larger fat droplets in the cytoplasm of hepatocytes - fatty degeneration. The appearance of large fat droplets shifts the nucleus to the periphery and displaces cytoplasmic organelles. This can lead to necrobiosis and then hepatocyte necrosis. Activation of macrophages that carry out phagocytosis of necrotic cells can lead to fibrosis, and in severe cases, to liver necrosis.
In the development of fatty hepatitis, two main points are distinguished: an increase in the intake of lipids and a decrease in their oxidation, primarily fatty acids. An increase in the supply of lipids to the liver, as already noted, occurs with a deficiency of carbohydrates, intense physical activity, diabetes mellitus, that is, with increased lipolysis in adipose and muscle tissue .. A decrease in the utilization of fatty acids occurs as a result of inhibition of their oxidation. This mechanism of steatosis is the leading one in various intoxications that decrease the activity of oxidative enzymes. These can be intoxications with bacterial poisons, chloroform, arsenic, phosphorus, carbon tetrachloride, nitrates, etc. Contributing factors are hypovitaminosis, hypoxia, acidosis, autoimmune processes.
For the transfer of fatty acids and their oxidation in the mitochondria of hepatocytes, carnitine, a transmembrane mitochondrial shuttle, is required. The assembly of VLDL, which carry endogenous fats, requires phospholipids containing choline. Both carnitine and choline require methyl groups. Therefore, all substances that are donors of methyl groups will contribute to the oxidation of fatty acids and the secretion of VLDL, which frees the liver from excess fat. Such substances are combined under the conditional name "lipotropic factors". These, in addition to carnitine and choline, include methionine, betaine, vitamins B6 and B12.
Phospholipids (for example, lecithin) contribute to a more active use of fatty acids. Their lipotropic effects are also mediated through their dispersing function.
Scientists have also shown that the cells of the excretory ducts of the pancreas contain a substance that has a lipotropic effect on the liver. They called it lipocaine. So far, it has not been singled out in its pure form, but its existence is still recognized by many authors.
Most lipotropic factors have their effect not only in the liver, but also in the kidneys, in the heart, in all organs and tissues in which fatty acid oxidation occurs and fatty infiltration is possible due to a decrease in this process.
8. The role of lipid peroxidation in cell damage
All organic substances undergo oxidation. During oxidative reactions, organic molecules are destroyed, and part of the released energy is stored in the form of ATP.
The end product of oxidative reactions is water, but the so-called reactive oxygen species are also formed - hydroxyl radical, superoxide anion, hydrogen peroxide. They are able to take electrons from organic molecules, turning them into active radicals and thus starting chain reactions of molecular damage. In leukocytes and macrophages, this mechanism serves as the basis for a “respiratory explosion”, during which bacteria and other objects of phagocytosis are destroyed. This is a useful feature. But in other cells, this leads to the self-destruction of organic molecules, including DNA. Lipid peroxidation (LPO) in cell membranes can lead to cell death. Unsaturated fatty acids are most susceptible to the action of reactive oxygen species.
LPO destroys cells in atherosclerosis, the development of tumors, nerve cells, in which there are many lipids. The body has systems to protect cells from reactive oxygen species: enzymes and vitamins that have an antioxidant effect. The enzyme superoxide dismutase (SOD) converts superoxide anions into hydrogen peroxide. The catalase enzyme breaks down hydrogen peroxide, which itself is listed as a damaging factor. The enzyme glutathione peroxidase destroys both hydrogen peroxide and lipid hydroperoxides, protecting membranes from damage. Selenium is the coenzyme of glutathione peroxidase; therefore, it, like vitamins E, C and β-carotenes, is classified as an antioxidant protection factor.
9. Eicosanoids
Eicosanoids are called biologically active substances that are synthesized in many cells from polyunsaturated fatty acids containing 20 carbon atoms (the word "eikosa" in Greek means 20).
Eicosanoids are "local hormones" because they break down quickly. Eicosanoids include prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and other derivatives. Polyene fatty acids, mainly arachidonic, from which eicosanoids are formed, are part of membrane phospholipids. They are separated from the membranes by the action of the enzyme phospholipase A, also built into the membranes. Enzyme activation can occur under the influence of many factors: histamine, cytokines, contact of the antigen-antibody complex with the cell surface, and mechanical impact. In the cytoplasm, arachidonic acid is converted into various eicosanoids ("arachidonic acid cascade"). The above etiological and pathogenetic factors occur during inflammation, therefore, the produced eicosanoids are referred to as cellular mediators of inflammation. Prostaglandins dilate arterioles, increase permeability cell wall, which stimulates extravasation and emigration of leukocytes. Leukotrienes are powerful chaetotaxis factors that enhance the movement of leukocytes to the site of inflammation for phagocytosis. Thus, the main signs of acute inflammation appear: redness (rubor), swelling (tumor), local temperature increase (calor), and pain (dolor). Pain occurs due to overstimulation of chemoreceptors by protons, histamine-like substances, and baroreceptors by exudate pressure.
Leukocytes formed by mast cells, alveolar macrophages and bronchial epithelial cells cause bronchospasm and secretion of mucus into the lumen of these tubes, thereby provoking an attack of bronchial asthma.
Thromboxane, produced by platelets during their activation, acts on the platelets themselves (autocrine mechanism), increasing their ability to aggregate, and at the same time stimulates the contraction of smooth muscle cells of blood vessels, contributing to their spasm. Thus, conditions are created for the formation of a thrombus and the prevention of bleeding in the area of damage to the vessel. Platelets are also activated when they encounter an atherosclerotic plaque. In this case, the formation of a thrombus leads to ischemia and the development of a heart attack. Other eicosanoids secreted by vascular endothelial cells prevent platelet aggregation and vasoconstriction. Thus, eicosanoids are involved in both coagulation and anticoagulation systems of the blood.
Synthetic analogues of prostaglandins are used as medicines. For example, the ability of PG E2 and PG F2 to stimulate uterine muscle contraction is used to induce labor. PG E1 and PG F1, by blocking type II histamine receptors in the cells of the gastric mucosa, inhibit the secretion of hydrochloric acid and thereby promote the healing of gastric and duodenal ulcers.
On the other hand, steroid and non-steroidal (aspirin, ibuprofen, indomethacin) anti-inflammatory drugs are used for inflammation. They inactivate enzymes that stimulate the formation of eicosanoids - inflammatory mediators. Steroid drugs have a much stronger anti-inflammatory effect than non-steroid drugs, they inhibit the activity of phospholipase A and reduce the synthesis of all types of eicosanoids, as they prevent the release of the substrate for the synthesis of eicosanoids - arachidonic acid.
10. Atherosclerosis
Atherosclerosis(from the Greek athere - slurry, skleros - hard) - progressive changes mainly in the inner lining of the arteries of the elastic and muscular-elastic type, consisting in excessive accumulation of LP and other blood components, the formation of fibrous tissue and complex changes occurring in it. The most affected are the abdominal aorta, coronary, carotid, renal arteries, arteries of the brain, mesentery, limbs. As a result of atherosclerotic lesions, the lumen of the arteries narrows, the blood supply to organs and tissues is disturbed, thrombosis, embolism, calcification, aneurysm of the vessel walls occur, often ending in heart attacks and hemorrhages.
Back in 1915, he drew attention to the positive correlation between the level of cholesterol in the blood and the possibility of developing atherosclerosis. As the pathogenesis of atherosclerosis was studied, the emphasis began to be placed on damage to endothelial cells, which initiates macrophage capture of blood lipids and their movement into the subendothelial space.
Damage to endotheliocytes can be triggered by lipid peroxidation radicals, toxins of both infectious and non-infectious origin, and immunopathological reactions. Alteration stimulates the penetration of macrophages, primarily monocytes, and platelets into the subendothelial space and the transport of LP there. In the vessel wall, LP are isolated from the antioxidant factors of blood plasma, therefore, they are subject to changes in LPO products. Macrophages phagocytize predominantly modified LDL and turn into so-called foam cells. The name is due to the fact that after processing the cut, the lipids are washed out and vacuoles remain, resembling foam. This is the first stage of atherogenesis - the formation of a fatty (lipid) strip. But the deposition of lipids in the wall of the arteries does not mean the transition of the process to the next stage - the formation of a fibrous plaque.
Fibrous plaque is called atheroma and fibroatheroma. First, an atheroma is formed, characterized by a significant accumulation of foam cells, smooth muscle cells, lymphocytes, and platelets. SMCs migrate from the medial membrane of the arteries under the action of macrophage and platelet biologically active substances - kinins, prostaglandins, chemotaxis factors, growth factors, etc. Under the influence of a growth factor, they actively multiply and synthesize collagen, elastin, proteoglycan - components of the intercellular substance. Atheroma is located in the inner lining of the arteries and grows, reducing the lumen of the vessel. It has a soft cholesterol core inside, as the trapped LDL is predominantly made up of cholesterol. Gradually, atheroma acquires a dense capsule, consisting of endothelial cells, SMCs, T-lymphocytes, fibrous tissue, thus turning into fibroatheroma.
The third stage is complex disorders with the development of complications of atherosclerosis. Fibroatheromas undergo calcification, ulceration, which activates thrombosis. Complications of these processes are ischemia and infarcts of organs. Violation of the integrity of the fibrous plaque leads to thinning of the vascular wall, hemorrhages and bleeding. In the aorta, the dissection of its walls is often noted and the development of an aneurysm - a protrusion. Aneurysms are very large. Aneurysms end with rupture of the aorta, or the formation of a large blood clot.
Thus, lipids are one of the main components of the cells of the animal organism. Lipids organize the work of each cell: they form a membrane through which all chemical signals, including hormonal ones, are perceived. Steroid hormones, many biologically active substances are of lipid origin. Adipose and nervous tissues are built mainly from lipids. In violation of lipid metabolism, dysregulatory pathologies develop in the form of ketosis, liver steatosis, atherosclerosis, obesity, etc.
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Lipids in the aquatic environment are insoluble, therefore, for their transport in the body, complexes of lipids with proteins are formed - lipoproteins (LP). There are exogenous and endogenous lipid transport. The exogenous transport includes the transport of dietary lipids, and the endogenous transport of lipids synthesized in the body.
There are several types of LP, but they all have a similar structure - a hydrophobic core and a hydrophilic layer on the surface. The hydrophilic layer is formed by proteins, which are called apoproteins, and amphiphilic lipid molecules, phospholipids and cholesterol. The hydrophilic groups of these molecules face the aqueous phase, while the hydrophobic groups face the core, which contains the transported lipids. Apoproteins perform several functions:
form the structure of lipoproteins (for example, B-48 - the main protein of XM, B-100 - the main protein of VLDL, LDL, LDL);
interact with receptors on the cell surface, determining which tissues will capture this type of lipoprotein (apoprotein B-100, E);
are enzymes or activators of enzymes acting on lipoproteins (C-II - LP-lipase activator, A-I - lecithin:cholesterol acyltransferase activator).
During exogenous transport, TAGs resynthesized in enterocytes together with phospholipids, cholesterol, and proteins form CM, and in this form are secreted first into the lymph, and then into the blood. In the lymph and blood, apoproteins E (apo E) and C-II (apo C-II) are transferred from HDL to CM, thus CM turns into "mature". HM are quite large, so after eating a fatty meal, they give the blood plasma an opalescent, milk-like appearance. Once in the circulatory system, HM quickly undergoes catabolism and disappears within a few hours. The time of destruction of HM depends on the hydrolysis of TAG under the action of lipoprotein lipase (LPL). This enzyme is synthesized and secreted by adipose and muscle tissues, cells of the mammary glands. Secreted LPL binds to the surface of endothelial cells of the capillaries of those tissues where it was synthesized. Secretion regulation is tissue specific. In adipose tissue, LPL synthesis is stimulated by insulin. This ensures the supply of fatty acids for synthesis and storage in the form of TAGs. In diabetes mellitus, when there is a deficiency of insulin, the level of LPL decreases. As a result, a large amount of LP accumulates in the blood. In muscle, where LPL is involved in supplying fatty acids for oxidation between meals, insulin inhibits the production of this enzyme.
Two factors necessary for LPL activity are distinguished on the HM surface: apoC-II and phospholipids. ApoC-II activates this enzyme, and phospholipids are involved in the binding of the enzyme to the HM surface. As a result of the action of LPL on TAG molecules, fatty acids and glycerol are formed. The main mass of fatty acids penetrates into tissues, where it can be deposited in the form of TAG (adipose tissue) or used as an energy source (muscles). Glycerol is transported by the blood to the liver, where during the absorption period it can be used for the synthesis of fats.
As a result of the action of LPL, the amount of neutral fats in HM is reduced by 90%, particle sizes are reduced, and apoC-II is transferred back to HDL. The resulting particles are called residual CM (remnants). They contain PL, cholesterol, fat-soluble vitamins, apoB-48 and apoE. Residual HM are taken up by hepatocytes that have receptors that interact with these apoproteins. Under the action of lysosome enzymes, proteins and lipids are hydrolyzed and then utilized. Fat-soluble vitamins and exogenous cholesterol are used in the liver or transported to other organs.
During endogenous transport, TAG and PL resynthesized in the liver are included in the composition of VLDLP, which includes apoB100 and apoC. VLDL are the main transport form for endogenous TAGs. Once in the blood, VLDL receive apoC-II and apoE from HDL and are exposed to LPL. During this process, VLDL is first converted into HDL and then into LDL. The main lipid of LDL becomes cholesterol, which in their composition is transferred to the cells of all tissues. The fatty acids formed during hydrolysis enter the tissues, and glycerol is transported by the blood to the liver, where it can again be used for the synthesis of TAG.
All changes in the content of lipoproteins in the blood plasma, characterized by their increase, decrease or complete absence, are combined under the name of dyslipoproteinemia. Dyslipoproteinemia can be either a specific primary manifestation of disorders in the metabolism of lipids and lipoproteins, or a concomitant syndrome in certain diseases of the internal organs (secondary dyslipoproteinemia). With successful treatment of the underlying disease, they disappear.
Hypolipoproteinemias include the following conditions.
1. Abetalipoproteinemia occurs with a rare hereditary disease - a defect in the apoprotein B gene, when the synthesis of apoB-100 proteins in the liver and apoB-48 in the intestine is disrupted. As a result, CM is not formed in the cells of the intestinal mucosa, and VLDLP is not formed in the liver, and fat droplets accumulate in the cells of these organs.
2. Familial hypobetalipoproteinemia: the concentration of drugs containing apoB is only 10-15% of the normal level, but the body is able to form HM.
3. Familial insufficiency of a-LP (Tangier's disease): practically no HDL is found in the blood plasma, and a large amount of cholesterol esters accumulate in the tissues, patients do not have apoC-II, which is an LPL activator, which leads to an increase in the concentration of TAG, which is characteristic of this condition in blood plasma.
Among hyperlipoproteinemias, the following types are distinguished.
Type I - hyperchylomicronemia. The rate of removal of HM from the bloodstream depends on the activity of LPL, the presence of HDL, which supply apoproteins C-II and E for HM, and the activity of transferring apoC-II and apoE to HM. Genetic defects in any of the proteins involved in the metabolism of CM lead to the development of familial hyperchylomicronemia - the accumulation of CM in the blood. The disease manifests itself in early childhood, is characterized by hepatosplenomegaly, pancreatitis, and abdominal pain. As a secondary sign, it is observed in patients with diabetes mellitus, nephrotic syndrome, hypothyroidism, and also in alcohol abuse. Treatment: diet low in lipids (up to 30 g/day) and high in carbohydrates.
Type II - familial hypercholesterolemia (hyper-b-lipoproteinemia). This type is divided into 2 subtypes: IIa, characterized by high levels of LDL in the blood, and IIb, with elevated levels of both LDL and VLDL. The disease is associated with a violation of the reception and catabolism of LDL (a defect in cellular receptors for LDL or a change in the structure of LDL), accompanied by an increase in the biosynthesis of cholesterol, apo-B and LDL. This is the most serious pathology in the exchange of drugs: the risk of developing coronary artery disease in patients with this type of disorder increases by 10-20 times compared with healthy individuals. As a secondary phenomenon, type II hyperlipoproteinemia can develop with hypothyroidism, nephrotic syndrome. Treatment: diet low in cholesterol and saturated fat.
Type III - dys-b-lipoproteinemia (broadband beta-lipoproteinemia) is caused by an abnormal composition of VLDL. They are enriched with free cholesterol and defective apo-E, which inhibits the activity of hepatic TAG lipase. This leads to impaired catabolism of HM and VLDL. The disease manifests itself at the age of 30-50 years. The condition is characterized by a high content of VLDL residues, hypercholesterolemia and triacylglycerolemia, xanthomas, atherosclerotic lesions of peripheral and coronary vessels are observed. Treatment: diet therapy aimed at weight loss.
Type IV - hyperpre-b-lipoproteinemia (hypertriacylglycerolemia). The primary variant is due to a decrease in LPL activity, an increase in the level of TAG in the blood plasma occurs due to the VLDL fraction, and no accumulation of CM is observed. Occurs only in adults, characterized by the development of atherosclerosis, first coronary, then peripheral arteries. The disease is often accompanied by a decrease in glucose tolerance. As a secondary manifestation occurs in pancreatitis, alcoholism. Treatment: diet therapy aimed at weight loss.
Type V - hyperpre-b-lipoproteinemia with hyperchylomicronemia. With this type of pathology, changes in blood lipoprotein fractions are complex: the content of CM and VLDL is increased, the severity of LDL and HDL fractions is reduced. Patients are often overweight, hepatosplenomegaly, pancreatitis may develop, atherosclerosis does not develop in all cases. As a secondary phenomenon, type V hyperlipoproteinemia can be observed in insulin-dependent diabetes mellitus, hypothyroidism, pancreatitis, alcoholism, type I glycogenosis. Treatment: diet therapy aimed at weight loss, a diet low in carbohydrates and fats.