Lecture"LIPID METABOLISM"

TRANSFORM Research Institute LIPIDS IN THE PROCESS OF DIGESTION

Lipids that are of great biological value for the human body (triacylglycerols, phospholipids, cholesterol, etc.) enter it as food components of biological origin.

For the digestion of lipids in the gastrointestinal tract, the following conditions are necessary:

presence of hydrolyzing lipids lipolytic enzymes;

optimal value for the manifestation of high catalytic activity of lipolytic enzymes pH media (neutral or slightly alkaline);

presence of emulsifiers.

All of the above conditions are created in the human intestine. The salivary glands are not able to produce enzymes that hydrolyze fats, as a result of which no noticeable digestion of fats occurs in the oral cavity. Digestion of fats also does not occur in the stomach of an adult, since pH gastric juice is close to 1.5, and the optimum pH environment for the action of gastric lipolytic enzyme - lipases is in the range of 5.5-7.5. It should be noted that pH gastric juice in newborns is about 5.0, which facilitates the digestion of emulsified triacylglycerols of milk by gastric lipase. In the intestine, hydrochloric acid of gastric juice is neutralized by bicarbonates of intestinal juice and fats are emulsified. Emulsification of lipids is carried out by CO2 bubbles released during the neutralization process with the participation of sodium or potassium salts of bile acids - cholic, 7-deoxycholic, glycincholic, taurocholic and others as surfactants. Bile acids enter the intestines from the gallbladder as part of bile. Emulsification is also facilitated by salts of fatty acids (soaps) formed during the hydrolysis of lipids. But the main role of surfactants in the emulsification of fats belongs to bile acids.

Anions of bile acids sharply reduce the surface tension at the fat-water interface, stabilize the resulting emulsion and form a transport complex with fatty acids, which includes their absorption into the intestinal walls. In addition, bile acids function as activators of lipolytic enzymes.

Triacylglycerols, which make up the bulk of food lipids, are hydrolyzed under the influence of pancreatic lipase, which enters the intestine in an inactive form and is then activated by bile acids. Active lipase has a hydrated hydrophilic region and a hydrophobic head in contact with triacylglycerols at the interface, where step-by-step hydrolysis occurs:

During hydrolysis, in the first stages, ester bonds 1 and 3 are rapidly hydrolyzed, and then the hydrolysis of 2-monoacylglycerol occurs slowly. The resulting 2-monoacylglycerol can then be absorbed by the intestinal wall and used for resynthesis triacylglycerols specific for this type of organism (see below).

They also take part in the hydrolysis of phospholipids phospholipases. Cholesterol esters supplied with food, which are rich in some foods (egg yolk, butter, caviar, etc.), are hydrolyzed cholesterol esterase to free cholesterol and fatty acids. Cholesterol esterase is active only in the presence of bile acids.

The products of hydrolytic breakdown of all dietary lipids are absorbed in the intestine. Glycerol and fatty acids with a short carbon chain (up to 10-12 C atoms) are highly soluble in water and pass into the blood in the form of an aqueous solution. Long-chain fatty acids (more than 14 C atoms) and monoacylglycerols are insoluble in water, therefore they are absorbed with the participation of bile acids, phospholipids and cholesterol, forming a mixture of 12.5: 2.5: 1.0 in the intestine, respectively. As a result, micelles are formed from lipid hydrolysis products surrounded by a hydrophilic shell of cholesterol, phospholipids and bile acids. Subsequently, the micelles disintegrate, and bile acids return to the intestines, completing 5-6 such cycles daily.

Lipids, before entering the lymph, undergo resynthesis, those. conversion to triacylglycerols. The importance of this process lies in the fact that newly synthesized specific fats differ in physical and chemical parameters from dietary lipids and are most suitable for a given organism. Since all differences in the composition of triacylglycerols are determined by the composition of fatty acids, lipid resynthesis uses its own long-chain fatty acids, which are synthesized in the intestine from precursors (only part of the absorbed fatty acids is suitable for resynthesis). Fatty acids form acyl-CoA, and then the acyl residues are transferred to monoacylglycerol with the participation of transacylase, with the sequential formation of di- and triacylglycerols from monoacylglycerol.

Transport of cholesterol and resynthesized lipids is carried out as part of lipoproteins, the protein part of which (apolipoprotein) makes them soluble in aqueous media.

The main metabolic pathways of fatty acids formed during the hydrolysis of dietary triacylglycerols are presented in drawing.

Intracellular lipid hydrolysis

Lipids are continuously renewed in tissues. The half-life of triacylglycerols, which play an important energy role in the body, ranges from 2 to 18 days. Other lipids (phospho-, sphingo-, glycolipids and cholesterol) predominantly act as components of biological membranes and are renewed less intensively. Lipid renewal requires their preliminary intracellular enzymatic hydrolysis - lipolysis.

It is generally accepted that triacylglycerols perform a role in lipid metabolism similar to that played by glycogen in carbohydrate metabolism, and higher fatty acids resemble glucose in their energy value. During physical activity and other conditions of the body that require increased energy expenditure, the consumption of triacylglycerols in adipose tissue as an energy reserve increases. However, only free fatty acids can be used as an energy source. Therefore, triacylglycerols are first hydrolyzed to glycerol and free fatty acids.

acids under the influence of specific tissue lipases. This process is controlled by the central nervous system and is triggered by a number of hormones (adrenaline, norepinephrine, etc.), which activate the hormone-sensitive triacylglycerol lipase. Triacylglycerol lipase breaks down triacylglycerol into diacylglycerol and fatty acid. Then upon action di- And monoacylglycerol lipases further lipolysis occurs to glycerol and fatty acids.

Glycerol formed as a result of lipolysis can participate in gluconeogenesis or be included in glycolysis with the preliminary formation of glycerol-3-phosphate under the influence of glycerol kinase and with the participation of ATF:

Then, under the action of dehydrogenase, glycerol-3-phosphate is converted into triose phosphates, which, in fact, are involved in gluconeogenesis or glycolysis.

Fatty acids, as part of a protein complex with blood albumin, enter the cells of various tissues and organs, where they undergo oxidation.

Biooxidation of fatty acids

The oxidation of fatty acids in organisms is an extremely important process; it can occur at the α-, β- and ω-carbon atoms of fatty acids. The main pathway of fatty acid oxidation in both animal and plant tissues is β-oxidation.

β-Oxidation of fatty acids. β-Oxidation of fatty acids was first studied in 1904 by F. Knoop. It was later found that β-oxidation occurs only in mitochondria. Thanks to the work of F. Linen and his colleagues (1954-1958), the main enzymatic processes of fatty acid oxidation were clarified. In honor of the scientists who discovered this pathway of fatty acid oxidation, the process β-oxidation is called Knoop-Linen cycle.

According to modern concepts, the process of fatty acid oxidation is preceded by their activation in the cytoplasm with the participation acyl-CoA synthetase and using ATP energy:

In the form of acyl-CoA, fatty acids enter mitochondria, in the matrix of which they undergo β-oxidation, which includes the sequence of enzymatic redox reactions listed below.

The first reaction in the fatty acid breakdown pathway is dehydrogenation with the formation of trans-2,3-unsaturated derivatives, catalyzed by various FAD-containing acyl-CoA dehydrogenases:

The second reaction - hydration of the double bond - is catalyzed enoyl-CoA - hydratase:

At the next (third) stage, dehydrogenation of the alcohol fragment occurs, which is carried out by the corresponding dehydrogenase and the oxidized form of the coenzyme NAD:

As a result of oxidation, β-oxoacid is formed, which is why the whole process is called β-oxidation.

The fourth and final reaction, catalyzed thiolase, is accompanied by redox cleavage of the C α -C β bond with the elimination of acetyl-CoA and the addition of a CoA residue at the site of the rupture of the intercarbon bond:

This reaction is called thiolysis and is highly exergonic, so the equilibrium in it is always shifted towards the formation of products.

Consistent repetition of this cycle of reactions leads to the complete breakdown of fatty acids with an even number of carbon atoms to acetyl-CoA. As a result of this process, acetyl-CoA, FADH 2 and NADH are formed. Next, acetyl-CoA enters the Krebs cycle, and reduced coenzymes enter the respiratory chain.

The peculiarity of the oxidation of fatty acids with an odd number of carbon atoms is that, along with the usual oxidation products, one molecule CH 3 -CH 2 -CO~SCoA (propionyl-CoA) is formed, which, during carboxylation, is converted into succinyl-CoA, which enters the Krebs cycle.

The characteristics of the oxidation of unsaturated fatty acids are determined by the position and number of double bonds in their molecules. To the point of the double bond, unsaturated fatty acids are oxidized in the same way as saturated fatty acids. If the double bond has the same trans configuration and location as enoyl-CoA, then oxidation proceeds along the usual path. Otherwise, an additional enzyme is involved in the reactions, which moves the double bond to the desired position and changes the configuration of the acid molecule.

β-oxidation of fatty acids releases a large amount of energy. The complete oxidation of one mole of a fatty acid containing 2n carbon atoms produces n moles of acetyl-CoA and (n-1) moles of (FADH 2 + NADH). The oxidation of FADH 2 produces 2ATP, and the oxidation of NADH produces 3ATP. Complete combustion of one mole of acetyl-CoA results in the formation of 12 moles of ATP.

Taking into account the fact that 1 mole of ATP is spent on the activation of a fatty acid, the ATP balance during complete oxidation of a fatty acid with an even number of carbon atoms can be expressed by the following formula:

For example, a mole of palmitic acid containing 16 carbon atoms yields 130 moles of ATP when oxidized. Thus, the energy value of fatty acids is much higher than that of glucose. However, during the oxidation of glucose, oxaloacetate is formed, which facilitates the inclusion of acetyl residues of fatty acids in the Krebs cycle. In this regard, in the biochemical literature there is an expression that “fats burn in the flame of carbohydrates.”

For ease of understanding, the β-oxidation cycle of fatty acids is schematically represented in drawing.

α-Oxidation of fatty acids. Along with β-oxidation, fatty acids with a sufficiently large number of carbon atoms (C13-C18) can undergo α-oxidation. This type of oxidation is especially common in plant tissues, but can also occur in some animal tissues. α-Oxidation is cyclic in nature, and the cycle consists of two reactions.

The first reaction consists of the oxidation of a fatty acid with hydrogen peroxide into the corresponding aldehyde and CO2 with the participation of a specific peroxidase:

As a result of this reaction, the hydrocarbon chain is shortened by one carbon atom.

The essence of the second reaction is the hydration and oxidation of the resulting aldehyde into the corresponding carboxylic acid under the action aldehyde dehydrogenase, containing the oxidized form of the coenzyme NAD:

The α-oxidation cycle then repeats again. Compared to β-oxidation, α-oxidation is energetically less favorable.

The ω-oxo acid is then oxidized to ω-dicarboxylic acid by the action of the corresponding dehydrogenase:

ω-Oxidation of fatty acids. In the liver of animals and in some microorganisms there is an enzyme system that provides ω-oxidation of fatty acids, i.e. oxidation at the terminal CH 3 group, designated by the letter ω. First, under the action of monooxygenase, hydroxylation occurs with the formation of ω-hydroxy acid:

The ω-dicarboxylic acid thus obtained is shortened at either end by β-oxidation reactions.

LIPID DIGESTION

Digestion is the hydrolysis of nutrients to their assimilable 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 occurs in several stages:

1) Lipids from solid food, under mechanical action and under the influence of bile surfactants, mix 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 work only in the aqueous phase. Lipids from liquid food (milk, broth, etc.) enter the body immediately in the form of an emulsion;

2) Under the action of lipases of digestive juices, hydrolysis of emulsion lipids occurs with the formation of water-soluble substances and simpler lipids;

3) Water-soluble substances released from the emulsion are absorbed and enter the blood. 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) occurs.

In infants, hydrolysis of TG with short and medium fatty acids, which come with liquid food in the form of an emulsion, begins here. Hydrolysis is carried out by lingual triglyceride lipase (“tongue lipase”, TGL), which is secreted by Ebner’s glands located on the dorsal surface of the tongue.

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 TGs, which contain mainly short- and medium-chain fatty acids (4-12 C). In adults, the contribution of “tongue lipase” to the digestion of TG is insignificant.

The main cells of the stomach produce gastric lipase, which is active at a neutral pH value, characteristic of the gastric juice of infants and young children, and is not active in adults (gastric juice pH ~ 1.5). This lipase hydrolyzes TG, cleaving off mainly fatty acids at the third carbon atom of glycerol. FAs and MGs formed in the stomach further participate in the emulsification of lipids in the duodenum.

Small intestine

The main process of lipid digestion occurs in the small intestine.

1. Emulsification of 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 is a viscous yellow-green liquid, has a pH = 7.3-8.0, contains H2O - 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, HCO3 - 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 intestines (deoxycholic, lithocholic, and about 20 others) from cholic and chenodeoxycholic acids under the influence 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 occurs. Emulsification is also facilitated by intestinal peristalsis and CO2 released during the interaction of chyme and bicarbonates: H+ + HCO3- → H2CO3 → H2O + CO2.

2. Hydrolysis of triglycerides is carried out by pancreatic lipase. Its optimum pH = 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 to 1-MG by isomerase. Most of the 1-MG is hydrolyzed by pancreatic lipase to glycerol and 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 through partial proteolysis. Colipase, with its hydrophobic domain, binds to the surface of the lipid droplet, and its hydrophilic domain helps bring the active center of pancreatic lipase as close as possible to TG, which accelerates their hydrolysis.

3. Hydrolysis of lecithin occurs with the participation of phospholipases (PL): A1, A2, C, D and lysophospholipase (lysoPL).

As a result of the action of these four enzymes, phospholipids are broken down into free fatty acids, glycerol, phosphoric acid and an amino alcohol or its analogue, for example, the amino acid serine, but some phospholipids are broken down by phospholipase A2 only into lysophospholipids and in this form can enter the intestinal wall.

PL A2 is activated by partial proteolysis with the participation of trypsin and hydrolyzes lecithin to lysolecithin. Lysolecithin is a good emulsifier. LysoPL hydrolyzes some of the lysolecithin to glycerophosphocholine. The remaining phospholipids are not hydrolyzed.

4. The hydrolysis of cholesterol 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 called mixed micelles in the intestinal lumen. Mixed micelles are constructed 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 contents of the small intestine. The stability of micelles is ensured mainly by bile salts, as well as monoglycerides and lysophospholipids.

Digestion regulation

Food stimulates the secretion of cholecystokinin (pancreozymin, a peptide hormone) from the cells of the small intestine mucosa into the blood. It causes the release of bile from the gallbladder and pancreatic juice from the pancreas into the lumen of the duodenum.

Acidic chyme stimulates the secretion of secretin (peptide hormone) from the cells of the small intestine mucosa into the blood. Secretin stimulates the secretion of bicarbonate (HCO3-) into the juice of the pancreas.

Peculiarities of lipid digestion in children

The intestinal secretory apparatus is generally formed by the time the child is born; the intestinal juice contains the same enzymes as in adults, but their activity is low. The process of fat digestion is especially intense due to the low activity of lipolytic enzymes. In breastfed children, bile-emulsified lipids are broken down by 50% under the influence of mother's milk lipase.

Digestion of liquid food lipids

ABSORPTION OF HYDROLYSIS PRODUCTS

1. Water-soluble products of lipid hydrolysis are absorbed in the small intestine without the participation of micelles. Choline and ethanolamine are absorbed in the form of CDP derivatives, phosphoric acid - in the form of Na+ and K+ salts, glycerol - in free form.

2. Fatty acids with short and medium chains are absorbed without the participation of micelles mainly in the small intestine, and some already in the stomach.

3. Water-insoluble products of lipid hydrolysis are absorbed in the small intestine with the participation of micelles. The micelles approach the brush border of the enterocytes, and the lipid components of the micelles (2-MG, 1-MG, fatty acids, cholesterol, lysolecithin, phospholipids, etc.) diffuse through the membranes into the cells.

Recycling of bile components

Together with the products of hydrolysis, bile components are absorbed - bile salts, phospholipids, cholesterol. Bile salts are absorbed most actively in the ileum. Bile acids then enter the liver through the portal vein, are again secreted from the liver into the gallbladder and then again participate in the emulsification of lipids. This bile acid pathway is called the “enterohepatic circulation.” Each molecule of bile acids undergoes 5-8 cycles per day, and about 5% of bile acids are excreted in feces.

DISORDERS IN DIGESTION AND ABSORPTION OF LIPIDS. STEATHORHEA

Impaired lipid digestion can occur with:

1) disturbance of the outflow of bile from the gallbladder (cholelithiasis, tumor). A decrease in bile secretion causes a violation of lipid emulsification, which leads to a decrease in lipid hydrolysis by digestive enzymes;

2) impaired secretion of pancreatic juice leads to a deficiency of pancreatic lipase and reduces lipid hydrolysis.

Impaired digestion of lipids inhibits their absorption, which leads to an increase in the amount of lipids in feces - steatorrhea (fatty stools) occurs. Normally, feces contain no more than 5% lipids. With steatorrhea, the absorption of fat-soluble vitamins (A, D, E, K) and essential fatty acids (vitamin F) is impaired, therefore hypovitaminosis of fat-soluble vitamins develops. Excess lipids bind non-lipid substances (proteins, carbohydrates, water-soluble vitamins) and prevent their digestion and absorption. Hypovitaminosis of water-soluble vitamins, protein and carbohydrate starvation occur. Undigested proteins undergo rotting in the large intestine.

34. Transport blood lipoproteins classification (by density, electrophoretic mobility, by apoproteins), place of synthesis, functions, diagnostic value (a – d):
)

TRANSPORT OF LIPIDS IN THE BODY

Lipid transport in the body occurs in two ways:

1) fatty acids are transported in the blood with the help of albumins;

2) TG, FL, HS, EHS, etc. Lipids are transported in the blood as part of lipoproteins.

Lipoprotein metabolism

Lipoproteins (LP) are spherical supramolecular complexes consisting of lipids, proteins and carbohydrates. LPs have a hydrophilic shell and a hydrophobic core. The hydrophilic shell includes proteins and amphiphilic lipids - PL, cholesterol. The hydrophobic core includes hydrophobic lipids - TG, cholesterol esters, etc. LPs are highly soluble in water.

Several types of lipids are synthesized in the body; they differ in chemical composition, are formed in different places and transport lipids in different directions.

Medicines are separated using:

1) electrophoresis, by charge and size, for α-LP, β-LP, pre-β-LP and CM;

2) centrifugation, by density, for HDL, LDL, LDLP, VLDL and CM.

The ratio and amount of LP in the blood depends on the time of day and nutrition. In the post-absorption period and during fasting, only LDL and HDL are present in the blood.

Main types of lipoproteins

Composition, % VLDL CM

(pre-β-LP) DILI

(pre-β-LP) LDL

(β-LP) HDL

Proteins 2 10 11 22 50

FL 3 18 23 21 27

EHS 3 10 30 42 16

TG 85 55 26 7 3

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 food lipids to tissues Transport of endogenous liver lipids to tissues Transport of endogenous liver lipids to tissues Transport of cholesterol

in tissue Removal of excess cholesterol

from fabrics

apo A, C, E

Place of formation of enterocyte hepatocyte in the blood from VLDL in the blood from LDLP hepatocyte

Apo B-48, C-II, E B-100, C-II, E B-100, E B-100 A-I C-II, E, D

Normal in blood< 2,2 ммоль/л 0,9- 1,9 ммоль/л

Apobelki

The proteins that make up the drug 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. Apo proteins can be peripheral (hydrophilic: A-II, C-II, E) and integral (have a hydrophobic section: B-48, B-100). Peripheral apos transfer between LPs, but integral apos do not. Apoproteins perform several functions:

Apoprotein Function Place of formation Localization

A-I Activator LCAT, formation of ECS liver HDL

A-II Activator of LCAT, formation of ECS HDL, CM

B-48 Structural (LP synthesis), receptor (LP phagocytosis) enterocyte CM

B-100 Structural (LP synthesis), receptor (LP phagocytosis) liver VLDL, LDPP, LDL

C-I Activator LCAT, formation of ECS Liver HDL, VLDL

C-II LPL activator, stimulates the hydrolysis of TG in the lipoprotein Liver HDL → CM, VLDL

C-III LPL inhibitor, inhibits TG hydrolysis in LP Liver HDL → CM, VLDL

D Cholesteryl ester transfer (CET) Liver HDL

E Receptor, phagocytosis of LP liver HDL → CM, VLDL, LDPP

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 capillaries of blood vessels. It hydrolyzes TG in the drug composition to glycerol and 3 fatty acids. With the loss of TG, cholesterol converts into residual cholesterol, and VLDL increases its density to LDLP and LDL.

Apo C-II LP activates LPL, and LP phospholipids are involved in the binding of LPL to the surface of the 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 values. In adipose tissue, LPL has Km 10 times greater than in the myocardium, therefore, adipose tissue absorbs fatty acids only when there is an excess of TG in the blood, and the myocardium constantly, even with a low concentration of TG in the blood. Fatty acids in adipocytes are used for the synthesis of TG, in the myocardium as a source of energy.

Hepatic lipase is located on the surface of hepatocytes; it does not act on mature cholesterol, but hydrolyzes TG in the LDPP.

Lecithin: cholesterol acyl transferase (LCAT) is located in HDL, it transfers acyl from lecithin to cholesterol to form ECL and lysolecithin. It is activated by apo A-I, A-II and C-I.

lecithin + CS → lysolecithin + ECS

ECS is immersed in the HDL core or transferred with the participation of apo D to other HDL.

Lipid transport receptors

The LDL receptor is a complex protein consisting of 5 domains and containing a carbohydrate part. The LDL receptor has ligands for the proteins ano B-100 and apo E, binds LDL well, worse than LDLP, VLDL, and residual CM containing these apos.

The LDL receptor is synthesized in almost all nuclear cells of the body. Activation or inhibition of protein transcription is regulated by the level of cholesterol in the cell. When there is a lack of cholesterol, the cell initiates the synthesis of the LDL receptor, and when there is an excess, on the contrary, it blocks it.

Hormones stimulate the synthesis of LDL receptors: insulin and triiodothyronine (T3), sex hormones, and glucocorticoids reduce it.

Michael Brown and Joseph Goldstein received the Nobel Prize in Physiology or Medicine in 1985 for their discovery of this critical receptor for lipid metabolism.

LDL receptor-like protein On the surface of cells in many organs (liver, brain, placenta), there is another type of receptor called “LDL receptor-like protein.” This receptor interacts with apo E and captures remnant (residual) CM and DILI. Since remnant particles contain cholesterol, this type of receptor also ensures its entry into tissues.

In addition to the entry of cholesterol into tissues through endocytosis of lipoproteins, a certain amount of cholesterol enters cells through diffusion from LDL and other lipoproteins upon their contact with cell membranes.

The normal concentration in the blood is:

LDL< 2,2 ммоль/л,

HDL > 1.2 mmol/l

Total lipids 4-8g/l,

HS< 5,0 ммоль/л,

TG< 1,7 ммоль/л,

Free fatty acids 400-800 µmol/l

CHYLOMICRON EXCHANGE

Lipids resynthesized in enterocytes are transported to tissues as part of CM.

· The formation of CM begins with the synthesis of apo B-48 on ribosomes. Apo B-48 and B-100 have a common gene. If only 48% of the information is copied from the gene onto mRNA, then apo B-48 is synthesized from it, if 100%, then apo B-100 is synthesized from it.

· With the ribosome, apo B-48 enters the ER lumen, where it is glycosylated. Then, in the Golgi apparatus, apo B-48 is surrounded by lipids and the formation of “immature”, nascent CMs occurs.

By exocytosis, nascent CMs are released into the intercellular space, enter the lymphatic capillaries and through the lymphatic system, through the main thoracic lymphatic duct they enter the blood.

· In lymph and blood, apo E and C-II are transferred from HDL to nascent CMs, and CMs turn into “mature” ones. ChMs are quite large in size, so they give the blood plasma an opalescent, milk-like appearance. Under the influence of LPL, TGs of CMs are hydrolyzed into fatty acids and glycerol. The bulk of fatty acids penetrate into the tissue, and glycerol is transported with the blood to the liver.

· When the amount of TG in CM decreases by 90%, they decrease in size, and apo C-II is transferred back to HDL, “mature” CM turn into “residual” remnant CM. Remnant CMs contain phospholipids, cholesterol, fat-soluble vitamins and apo B-48 and E.

· Through the LDL receptor (capture of apo E, B100, B48), remnant cholesterol is captured by hepatocytes. Through endocytosis, residual CMs enter the cells and are digested in lysosomes. ChMs disappear from the blood within a few hours.

I approve

Head department prof., doctor of medical sciences

Meshchaninov V.N.

_____‘’_____________2005

Lecture No. 12 Topic: Digestion and absorption of lipids. Transport of lipids in the body. Lipoprotein metabolism. Dyslipoproteinemia.

Faculties: therapeutic and preventive, medical and preventive, pediatric.

Lipids is a structurally diverse group of organic substances that are united by a common property - solubility in non-polar solvents.

Classification of lipids

Based on their ability to hydrolyze in an alkaline environment to form soaps, lipids are divided into saponified (contain fatty acids) and unsaponifiable (single-component).

Saponifiable lipids contain mainly the 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 (an ester of a higher monohydric alcohol and a fatty acid);

2) triacylglycerides, diacylglycerides, monoacylglycerides (ester of glycerol and fatty acids). A person weighing 70 kg has about 10 kg of TG.

3) ceramides (ester of sphingosine and C18-26 fatty acid) - form 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, containing an unsaturated monohydric higher alcohol, phosphoric acid and amino alcohol) - phosphatidal ethanolamines, phosphatidalserines, 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 (ester of sphingosine and C18-26 fatty acid, contains hexose (glucose or galactose) to which sulfuric acid is attached at the 3rd position). Abundant in white matter;

c) gangliosides (ester of sphingosine and C18-26 fatty acid, contains an oligosaccharide of 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 various functions in the body:

Structural. Complex lipids and cholesterol are amphiphilic and form all cell membranes; Phospholipids line the surface of the alveoli and form the shell of lipoproteins. Sphingomyelins, plasmalogens, and glycolipids form myelin sheaths and other membranes of nerve tissue.

Energy. In the body, up to 33% of all ATP energy is generated by lipid oxidation;

Antioxidant. Vitamins A, D, E, K prevent SRO;

Storage. Triacylglycerides are the storage form of fatty acids;

Protective. Triacylglycerides, contained in 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 regulating immunogenesis, hemostasis, nonspecific resistance of the body, inflammatory, allergic, proliferative reactions. Steroid hormones are formed from cholesterol: sex hormones and corticoids;

Vitamin D and bile acids are synthesized from cholesterol;

Digestive. Bile acids, phospholipids, cholesterol provide emulsification and absorption of lipids;

Information. 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 essential and come only from food.

Principles of rationing lipids in nutrition

A person needs to eat 80-100g of lipids per day, of which 25-30g of vegetable oil, 30-50g of butter and 20-30g of fat of animal origin. Vegetable oils contain many polyene essential (linoleic up to 60%, linolenic) fatty acids and phospholipids (removed during refining). Butter contains a lot of vitamins A, D, E. Food lipids contain mainly triglycerides (90%). About 1 g of phospholipids and 0.3-0.5 g of cholesterol are supplied with food per day, mainly in the form of esters.

The need for dietary lipids depends on age. For infants, the main source of energy is lipids, and for adults it is glucose. Newborns 1 to 2 weeks require lipids 1.5 g/kg, children – 1g/kg, adults – 0.8 g/kg, elderly – 0.5 g/kg. The need for lipids increases in the cold, during physical activity, during recovery and during pregnancy.

All natural lipids are easily 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 beneficial lipids, resulting in the formation of toxic products of fatty acid oxidation and carcinogenic substances.

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 food, atherosclerosis develops and the risk of breast and colon cancer increases.

Digestion and absorption of lipids

Digestion This is the hydrolysis of nutrients to their assimilable 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 occurs in several stages:

1) Lipids from solid food, under mechanical action and under the influence of bile surfactants, mix 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. Lipids from liquid food (milk, broth, etc.) enter the body immediately in the form of an emulsion;

2) Under the action of lipases of digestive juices, hydrolysis of emulsion lipids occurs with the formation of water-soluble substances and simpler lipids;

3) Water-soluble substances released from the emulsion are absorbed and enter the blood. 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) occurs. 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 Ebner’s 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 TGs, which contain mainly short- and medium-chain fatty acids (4-12 C). In adults, the contribution of “tongue lipase” to the digestion of TG is insignificant.

The main cells of the stomach produce gastric lipase , which is active at a neutral pH value, characteristic of the gastric juice of infants and young children, and is not active in adults (gastric juice pH ~ 1.5). This lipase hydrolyzes TG, cleaving off mainly fatty acids at the third carbon atom of glycerol. FAs and MGs formed in the stomach further participate 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 influence 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 this is a viscous yellow-green liquid, has a 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 intestines (deoxycholic, lithocholic, and about 20 others) from cholic and chenodeoxycholic acids under the influence 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 occurs. 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 triglycerides carried out by pancreatic lipase. Its optimum pH = 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 to 1-MG by isomerase. Most of the 1-MG is hydrolyzed by pancreatic lipase to glycerol and fatty acid.

3. Hydrolysis lecithin occurs with the participation of phospholipases (PL): A 1, A 2, C, D and lysophospholipase (lysoPL).

PL A 2 is activated by partial proteolysis with the participation of trypsin and hydrolyzes lecithin to lysolecithin. Lysolecithin is a good emulsifier. LysoPL hydrolyzes part of lysolecithin to glycerophosphocholine. The remaining phospholipids are not hydrolyzed.

4. Hydrolysis cholesterol esters cholesterol and fatty acids are processed by cholesterol esterase, an enzyme of the pancreas and intestinal juice.

There is no doubt that in everyday food made from fat Neutral fats, known as triglycerides, predominate, each molecule containing a glycerol core and side chains consisting of three fatty acids. Neutral fats are the main component of animal foods, and plant foods contain very little of them.

In normal food there are small amounts of phospholipids, cholesterol and cholesterol esters. Phospholipids and cholesterol esters contain fatty acids and therefore can be considered fats. However, cholesterol is a representative of sterols and does not contain fatty acids, but exhibits some physical and chemical properties of fats; Moreover, it is produced from fats and is easily converted into them. Therefore, from a nutritional point of view, cholesterol is considered as fat.

Digestion of fats in the intestines. A small amount of triglycerides is digested in the stomach by the action of lingual lipase, which is secreted by the glands of the tongue in the mouth and swallowed along with saliva. The amount of fat digested in this way is less than 10%, and therefore not significant. The main digestion of fats occurs in the small intestine, as discussed below.

Emulsification of fats bile acids and lecithin. The first step in fat digestion is to physically break down the fat droplets into small particles, since water-soluble enzymes can only act on the surface of the droplet. This process is called fat emulsification and begins in the stomach by mixing fats with other products of digestion of gastric contents.

Next is the main stage emulsification occurs in the duodenum under the influence of bile, a liver secretion that does not contain digestive enzymes. However, bile contains a large amount of bile salts, as well as a phospholipid - lecithin. These components, especially lecithin, are extremely important for the emulsification of fats. The polar species (the place where water ionizes) of bile salts and lecithin molecules are highly soluble in water, while most of the remainder of these molecules are highly soluble in fat.

Thus, fat soluble portions liver secretions dissolve in the surface layer of fat droplets along with the protruding polar part. In turn, the protruding polar part is soluble in the surrounding aqueous phase, which significantly reduces the surface tension of the fats and makes them also soluble.

When surface tension drops of insoluble liquid low, water-insoluble liquid during movement is much more easily broken into many small particles than with a higher surface tension. Therefore, the main function of bile salts and lecithin is to make fat droplets capable of being easily crushed when mixed with water in the small intestine. This action is similar to the action of synthetic detergents widely used in households to remove grease.

Every time the result mixing in the small intestine The diameter of the fat droplets decreases significantly, so the total fat surface increases many times. Because the average diameter of fat particles in the intestines after emulsification is less than 1 micron, the total fat surface area formed as a result of the emulsification process increases 1000 times.

Lipase enzyme is water soluble and can only act on the surface of fat droplets. From this it is clear how significant the detergent role of lecithin and bile salts is in the digestion of fats.

Digestion of proteins

Proteolytic enzymes involved in the digestion of proteins and peptides are synthesized and secreted into the cavity of the digestive tract in the form of proenzymes, or zymogens. Zymogens are inactive and cannot digest the cells' own proteins. Proteolytic enzymes are activated in the intestinal lumen, where they act on food proteins.

In human gastric juice there are two proteolytic enzymes - pepsin and gastrixin, which are very similar in structure, which indicates their formation from a common precursor.

Pepsin is formed in the form of a proenzyme - pepsinogen - in the main cells of the gastric mucosa. Several pepsinogens with similar structures have been isolated, from which several varieties of pepsin are formed: pepsin I, II (IIa, IIb), III. Pepsinogens are activated with the help of hydrochloric acid secreted by the parietal cells of the stomach, and autocatalytically, i.e. with the help of the resulting pepsin molecules.

Pepsinogen has a molecular weight of 40,000. Its polypeptide chain includes pepsin (molecular weight 34,000); a fragment of a polypeptide chain that is a pepsin inhibitor (molecular weight 3100), and a residual (structural) polypeptide. The pepsin inhibitor has sharply basic properties, as it consists of 8 lysine residues and 4 arginine residues. Activation consists of the cleavage of 42 amino acid residues from the N-terminus of pepsinogen; First, the residual polypeptide is cleaved off, followed by the pepsin inhibitor.

Pepsin belongs to carboxyproteinases containing dicarboxylic amino acid residues in the active site with an optimum pH of 1.5-2.5.

Pepsin substrates are proteins, either native or denatured. The latter are easier to hydrolyze. Denaturation of food proteins is ensured by cooking or the action of hydrochloric acid. The following should be noted biological functions of hydrochloric acid:

pepsinogen activation;
creating an optimum pH for the action of pepsin and gastricsin in gastric juice;
denaturation of food proteins;
antimicrobial action.

The own proteins of the stomach walls are protected from the denaturing effect of hydrochloric acid and the digestive action of pepsin by a mucous secretion containing glycoproteins.

Pepsin, being an endopeptidase, quickly cleaves internal peptide bonds in proteins formed by the carboxyl groups of aromatic amino acids - phenylalanine, tyrosine and tryptophan. The enzyme hydrolyzes peptide bonds between leucine and dicarboxylic amino acids more slowly: in the polypeptide chain.

Gastricin close to pepsin in molecular weight (31,500). Its optimum pH is about 3.5. Gastricsin hydrolyzes peptide bonds formed by dicarboxylic amino acids. The pepsin/gastricsin ratio in gastric juice is 4:1. In case of peptic ulcer, the ratio changes in favor of gastricsin.

The presence of two proteinases in the stomach, of which pepsin acts in a strongly acidic environment, and gastrixin in a moderately acidic environment, allows the body to more easily adapt to dietary patterns. For example, vegetable and dairy nutrition partially neutralizes the acidic environment of gastric juice, and the pH favors the digestive action of gastricsin rather than pepsin. The latter breaks down the bonds in food protein.

Pepsin and gastrixin hydrolyze proteins into a mixture of polypeptides (also called albumoses and peptones). The depth of protein digestion in the stomach depends on the length of time food is in it. Usually this is a short period, so the bulk of the proteins are broken down in the intestines.

Intestinal proteolytic enzymes. Proteolytic enzymes enter the intestine from the pancreas in the form of proenzymes: trypsinogen, chymotrypsinogen, procarboxypeptidases A and B, proelastase. Activation of these enzymes occurs through partial proteolysis of their polypeptide chain, i.e., the fragment that masks the active center of proteinases. The key process of activation of all proenzymes is the formation of trypsin (Fig. 1).

Trypsinogen coming from the pancreas is activated by enterokinase, or enteropeptidase, which is produced by the intestinal mucosa. Enteropeptidase is also secreted as a kinase gene precursor, which is activated by bile protease. Activated enteropeptidase quickly converts trypsinogen into trypsin, trypsin carries out slow autocatalysis and quickly activates all other inactive precursors of pancreatic juice proteases.

The mechanism of trypsinogen activation is the hydrolysis of one peptide bond, resulting in the release of an N-terminal hexapeptide called trypsin inhibitor. Next, trypsin, breaking peptide bonds in other proenzymes, causes the formation of active enzymes. In this case, three types of chymotrypsin, carboxypeptidase A and B, and elastase are formed.

Intestinal proteinases hydrolyze peptide bonds of food proteins and polypeptides formed after the action of gastric enzymes to free amino acids. Trypsin, chymotrypsins, and elastase, being endopeptidases, promote the rupture of internal peptide bonds, breaking up proteins and polypeptides into smaller fragments.

Trypsin hydrolyzes peptide bonds formed mainly by the carboxyl groups of lysine and arginine; it is less active against peptide bonds formed by isoleucine.
Chymotrypsins are most active against peptide bonds, in the formation of which tyrosine, phenylalanine, and tryptophan take part. In terms of specificity of action, chymotrypsin is similar to pepsin.
Elastase hydrolyzes those peptide bonds in polypeptides where proline is located.
Carboxypeptidase A is a zinc-containing enzyme. It cleaves C-terminal aromatic and aliphatic amino acids from polypeptides, while carboxypeptidase B cleaves only C-terminal lysine and arginine residues.

Enzymes that hydrolyze peptides are also present in the intestinal mucosa, and although they can be secreted into the lumen, they function predominantly intracellularly. Therefore, hydrolysis of small peptides occurs after they enter the cells. Among these enzymes are leucine aminopeptidase, which is activated by zinc or manganese, as well as cysteine, and releases N-terminal amino acids, as well as dipeptidases, which hydrolyze dipeptides into two amino acids. Dipeptidases are activated by cobalt, manganese and cysteine ions.

A variety of proteolytic enzymes leads to the complete breakdown of proteins into free amino acids, even if the proteins were not previously exposed to pepsin in the stomach. Therefore, patients after surgery for partial or complete removal of the stomach retain the ability to absorb food proteins.

Mechanism of digestion of complex proteins

The protein part of complex proteins is digested in the same way as simple proteins. Their prosthetic groups are hydrolyzed depending on their structure. The carbohydrate and lipid components, after they are cleaved from the protein part, are hydrolyzed by amylolytic and lipolytic enzymes. The porphyrin group of chromoproteins is not cleaved.

Of interest is the process of breakdown of nucleoproteins, which are rich in some foods. The nucleic component is separated from the protein in the acidic environment of the stomach. In the intestine, polynucleotides are hydrolyzed by intestinal and pancreatic nucleases.

RNA and DNA are hydrolyzed under the action of pancreatic enzymes - ribonuclease (RNase) and deoxyribonuclease (DNase). Pancreatic RNase has an optimum pH of about 7.5. It cleaves internal internucleotide bonds in RNA. In this case, shorter polynucleotide fragments and cyclic 2,3-nucleotides are formed. Cyclic phosphodiester bonds are hydrolyzed by the same RNase or intestinal phosphodiesterase. Pancreatic DNase hydrolyzes internucleotide bonds in DNA supplied with food.

The products of polynucleotide hydrolysis - mononucleotides - are exposed to the action of intestinal wall enzymes: nucleotidase and nucleosidase:

These enzymes have relative group specificity and hydrolyze both ribonucleotides and ribonucleosides and deoxyribonucleotides and deoxyribonucleosides. Nucleosides, nitrogenous bases, ribose or deoxyribose, H 3 PO 4 are absorbed.