Abstract Digestion and absorption of lipids. Transport of lipids in the body

Lipids are transported in the aqueous phase of the blood as part of special particles - lipoproteins. The surface of the particles is hydrophilic and formed by proteins, phospholipids and free cholesterol. Triacylglycerols and cholesterol esters form the hydrophobic core.

Proteins in lipoproteins are usually called apoproteins; there are several types of them - A, B, C, D, E. In each class of lipoproteins there are corresponding apo-proteins.

proteins that perform structural, enzymatic and cofactor functions.

Lipoproteins differ in the ratio of triacylglycerols, cholesterol and its esters, phospholipids, and as complex proteins they consist of four classes.

o high density lipoproteins (HDL, α-lipoproteins, α-LP).

Chylomicrons and VLDL are primarily responsible for the transport of fatty acids within TAG. High and low density lipoproteins are responsible for the transport of cholesterol and fatty acids in the composition of cholesterol esters.

TRANSPORT OF TRIacylGLYCEROLS IN THE BLOOD

Transport TAG from the intestines to the tissues(exogenous TAG) is carried out in the form of chylomicrons, from liver to tissues(endogenous TAG) – in the form of very low density lipoproteins.

IN In the transport of TAG to tissues, the following sequence of events can be distinguished:

1. Formation of immature primary CMs in intestines.

2. Movement of primary CMs through lymphatic ducts in blood .

3. Maturation of CM in blood plasma - obtaining proteins apoC-II and apoE from HDL.

4. Interactionlipoprotein lipase endothelium and loss of most of the TAG. Educational

reduction of residual chemical substances.

5. Transition of residual chemical substances into hepatocytes and complete collapse of their structure.

6. Synthesis of TAG in the liver from food glucose Use of TAGs that came as part of residual chemical substances.

7. Formation of primary VLDL in liver

8. Maturation of VLDL in blood plasma - obtaining apoC-II and apoE proteins from HDL.

9. Interactionlipoprotein lipase endothelium and loss of most of the TAG. Formation of residual VLDL (otherwise known as intermediate-density lipoproteins, IDL).

10. Residual VLDL passes into hepatocytes and completely disintegrate or remain

V blood plasma. After exposure to hepatic TAG lipases in the liver sinusoids convert VLDL into LDL.

The formation of lipoproteins (LP) in the body is a necessity due to the hydrophobicity (insolubility) of lipids. The latter are encased in a protein shell formed by special transport proteins - apoproteins, which ensure the solubility of lipoproteins. In addition to chylomicrons (CM), 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. Fine separation 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, because lipoproteins are supramolecular formations based on non-covalent bonds. In this case, CM 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 are HDL, which contains the largest amount of proteins.

Another classification of LP is based on electrophoretic mobility. During electrophoresis in a polyacrylamide gel, CM, as the largest particles, remains at the start, VLDL forms the pre-β - LP fraction, LDPP and CPDL - the β - LP fraction, HDL - the α - LP fraction.

All drugs are built from a hydrophobic core (fats, cholesteryl esters) and a hydrophilic shell, represented by proteins, as well as phospholipids and cholesterol. Their hydrophilic groups face the aqueous phase, and their hydrophobic parts face the center, the core. Each type of lipid is formed in different tissues and transports certain lipids. Thus, CMs transport fats obtained from food from the intestines into tissues. CMs consist of 84-96% exogenous triacylglycerides. In response to a fatty load, capillary endothelial cells release the enzyme lipoprotein lipase (LPL) into the blood, which hydrolyzes HM fat molecules to glycerol and fatty acids. Fatty acids are transported to 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 support macrophage activity. It is no coincidence that badger and bear fat are used in folk medicine for pulmonary pathologies, and northern peoples living in harsh climatic conditions rarely suffer from bronchitis and pneumonia when consuming fatty foods.

On the other hand, high LPL activity in the capillaries of adipose tissue promotes obesity. There is also evidence that during fasting it decreases, but the activity of muscle LPL increases.

Residual CM particles are captured by endocytosis by hepatocytes, where they are broken down by lysosome enzymes to amino acids, fatty acids, glycerol, and cholesterol. One part of the cholesterol and other lipids is directly excreted into bile, the other is converted into bile acids, and the third is included in VLDL. The latter contain 50-60% of endogenous triacylglycerides, therefore, after their secretion into the blood, they are exposed, like CM, to the action of lipoprotein lipase. As a result, VLDL loses TAG, which is then used by fat and muscle cells. During the catabolism of VLDL, the relative percentage of cholesterol and its esters (EC) increases (especially when consuming foods rich in cholesterol), and VLDL is converted into LDLP, which in many mammals, especially rodents, is taken up by the liver and completely broken down in hepatocytes. In humans, primates, birds, and pigs, a large part of the LDPP in the blood, not captured by hepatocytes, is converted into LDL. This fraction is the richest in cholesterol and cholesterol, and since high cholesterol is one of the first risk factors for the development of atherosclerosis, LDL is called the most atherogenic fraction of LP. LDL cholesterol is used by adrenal cells and gonads to synthesize steroid hormones. LDL supplies cholesterol to hepatocytes, renal epithelium, lymphocytes, and cells of the vascular wall. Due to the fact that cells themselves are capable of synthesizing cholesterol from acetyl coenzyme A (AcoA), there are physiological mechanisms that protect tissue from excess cholesterol: inhibition of the production of their own internal cholesterol and receptors for lipid apoproteins, since any endocytosis is receptor mediated. The 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 the vascular wall, binding excess cholesterol and removing it from the tissues, and they themselves become mature HDL. Part of the EC passes directly in the plasma from HDL to VLDL and LDLP. Ultimately, all LPs are broken down by the lysosomes of hepatocytes. Thus, almost all of the “extra” cholesterol enters the liver and is excreted from it as part of bile into the intestines, being removed with feces.

Lipids are insoluble in an aqueous environment, therefore, for their transport in the body, complexes of lipids with proteins are formed - lipoproteins (LP). There are exo- and endogenous lipid transport. Exogenous includes the transport of lipids received from food, and endogenous includes the movement 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 called apoproteins and amphiphilic lipid molecules - phospholipids and cholesterol. The hydrophilic groups of these molecules face the aqueous phase, and the hydrophobic groups face the core, in which the transported lipids are located. Apoproteins perform several functions:
· form the structure of lipoproteins (for example, B-48 is the main protein of XM, B-100 is the main protein of VLDL, LDPP, LDL);
· interact with receptors on the surface of cells, determining which tissues will capture this type of lipoprotein (apoprotein B-100, E);
· are enzymes or activators of enzymes acting on lipoproteins (C-II - activator of lipoprotein lipase, A-I - activator of lecithin: cholesterol acyltransferase).
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 lymph and blood, apoproteins E (apo E) and C-II (apo C-II) are transferred from HDL to CM, thus turning CM into “mature” ones. ChMs are quite large in size, so after eating a fatty meal they give the blood plasma an opalescent, milk-like appearance. Once in the circulatory system, CMs quickly undergo catabolism and disappear within a few hours. The time of destruction of CM depends on the hydrolysis of TAG under the action of lipoprotein lipase (LPL). This enzyme is synthesized and secreted by adipose and muscle tissues, and mammary gland cells. Secreted LPL binds to the surface of the endothelial cells of the capillaries of the tissues where it was synthesized. The regulation of secretion 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 TAG. In diabetes mellitus, when there is a deficiency of insulin, LPL levels decrease. As a result, a large amount of LP accumulates in the blood. In muscles, where LPL is involved in supplying fatty acids for oxidation between meals, insulin inhibits the formation of this enzyme.
On the surface of CM, there are 2 factors necessary for LPL activity: apoC-II and phospholipids. ApoC-II activates this enzyme, and phospholipids are involved in binding the enzyme to the surface of CM. As a result of the action of LPL on TAG molecules, fatty acids and glycerol are formed. The bulk of fatty acids penetrate into tissues, where they 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 CM decreases by 90%, particle sizes decrease, 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 CMs are captured by hepatocytes, which 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 VLDL, which includes apoB100 and apoC. VLDL is the main transport form for endogenous TAG. Once in the blood, VLDL receives apoC-II and apoE from HDL and is exposed to LPL. During this process, VLDL is first converted into LDLP 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 drugs in the blood plasma, characterized by their increase, decrease or complete absence, are combined under the name dislipoproteinemia. 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 internal organs (secondary dyslipoproteinemia). With successful treatment of the underlying disease, they disappear.
Hypolipoproteinemia includes the following conditions.
1. Abetalipoproteinemia occurs due to a rare hereditary disease - a defect in the apoprotein B gene, when the synthesis of proteins apoB-100 in the liver and apoB-48 in the intestine is disrupted. As a result, CMs are not formed in the cells of the intestinal mucosa, and VLDL is not formed in the liver, and droplets of fat 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 capable of forming cholesterol.
3. Familial a-LP deficiency (Tangier disease): practically no HDL is found in the blood plasma, and a large amount of cholesterol esters accumulates in the tissues; patients lack apoC-II, which is an activator of LPL, which leads to an increase in TAG concentration characteristic of this condition in blood plasma.
Among hyperlipoproteinemias, the following types are distinguished.
Type I - hyperchylomicronemia. The rate of removal of CM from the bloodstream depends on the activity of LPL, the presence of HDL, which supplies apoproteins C-II and E for CM, and the activity of transferring apoC-II and apoE to CM. Genetic defects of any of the proteins involved in the metabolism of CMs lead to the development of familial hyperchylomicronemia - the accumulation of CMs in the blood. The disease manifests itself in early childhood and is characterized by hepatosplenomegaly, pancreatitis, and abdominal pain. As a secondary symptom, it is observed in patients with diabetes mellitus, nephrotic syndrome, hypothyroidism, and also with 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 a high level of LDL in the blood, and IIb, with increased levels of both LDL and VLDL. The disease is associated with impaired reception and catabolism of LDL (defect in cellular receptors for LDL or changes in the structure of LDL), accompanied by increased biosynthesis of cholesterol, apo-B and LDL. This is the most serious pathology in drug metabolism: the risk of developing coronary artery disease in patients with this type of disorder increases 10-20 times compared to healthy individuals. As a secondary phenomenon, type II hyperlipoproteinemia can develop with hypothyroidism and nephrotic syndrome. Treatment: Diet low in cholesterol and saturated fat.
Type III - dys-b-lipoproteinemia (broadband betalipoproteinemia) 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 disturbances in the catabolism of cholesterol 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; accumulation of CM is not observed. It occurs only in adults and is characterized by the development of atherosclerosis, first of the coronary, then of the peripheral arteries. The disease is often accompanied by decreased glucose tolerance. As a secondary manifestation, it occurs in pancreatitis and alcoholism. Treatment: diet therapy aimed at weight loss.
Type V – hyperpre-b-lipoproteinemia with hyperchylomicronemia. With this type of pathology, changes in blood lipid fractions are complex: the content of cholesterol and VLDL is increased, the severity of LDL and HDL fractions is reduced. Patients are often overweight; hepatosplenomegaly and 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, and type I glycogenosis. Treatment: diet therapy aimed at weight loss, a diet low in carbohydrates and fats.

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 with nut 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(his OH group), squirrels. The hydrophilicity of the surface layer lipids is designed to ensure the solubility of the lipoprotein particle in the blood plasma,
the "core" is formed by non-polar cholesterol esters(HS) and triacylglycerols(TAG), which are transported fats. Their ratio varies in different types of lipoproteins. Also facing the center are the fatty acid residues of phospholipids and the cyclic part of cholesterol.

Scheme of the structure of any transport lipoprotein

There are four main classes of lipoproteins:

high density lipoproteins (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 (CM).

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 storage or use as energy substrates,
polyunsaturated fatty acids in 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 as part of TAG. High and low density lipoproteins - for the transport of free cholesterol And fatty acids as part of its ethers. HDL is also capable of donating part of its phospholipid membrane to cells.

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 usually called apowhites, 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– adds triacylcerols,
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 lipoprotein metabolic enzymes 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 DISORDERS IN ANIMAL BODIES

lecture

Recommended by the educational and methodological commission of the Faculty of Veterinary Medicine of the Moscow State Academy of Veterinary Medicine and Biology named after. for students studying in specialty 111201 - Veterinary Medicine

Moscow 2009

UDC 636: 612.015

Associate Professor of the Department of Pathological Physiology named after. 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 basic 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 of April 9, 2009).

Abbreviations used………………………..………………4

1. The importance of lipids in the body………………………….………. 5

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 lipostat…………………………………………….11

7. Ketosis and liver steatosis………………… ……………………….12

8. The role of lipid peroxidation in cell damage...15

9. Eicosanoids……………………………………………………16

10. Atherosclerosis………………………………………………………17

Bibliography……………………………………………………… …18

Abbreviations used.

ACoA – acetyl coenzyme A

BAS – biologically active substances

SMCs – smooth muscle cells

VFA - volatile fatty acids

LP - lipoproteins

LPL – lipoprotein lipase

LDL – low density lipoproteins

VLDL – very low density lipoproteins

DILI – Intermediate Density Lipoproteins

LPO – lipid peroxidation

FFA - free fatty acids

TAG – triacylglycerides (fats)

FLIP – phospholipids

HM – chylomicrons

CN - cholesterol

TCA cycle - tricarboxylic acid cycle

EC - cholesterol esters

Lipids– a group of hydrophobic substances soluble in organic solvents (ether, benzene, acetone), constructed 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 contain residues of compounds of other classes - phosphoric acid, nitrogenous bases, carbohydrates. Complex lipids include phospholipids, sphingolipids, etc.

Triacylglycerides (TAG) are mainly found in subcutaneous fatty tissue, performing reserve-energy, heat-insulating and shock-absorbing functions. The fat pad around the kidneys, heart, and eyeball also plays an important shock-absorbing role. During the oxidation of TAG, not only the largest amount of energy is released, but also water, which is important for obtaining endogenous moisture by animals in arid places and deserts (camels, gerbils, etc.). For energy needs, skeletal muscles partially, and the myocardium mainly uses fatty acids, the brain uses 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 contains lipids up to 50% of dry matter, mainly phospholipids (FLIP) and sphingolipids.

Nutritional lipid deficiency is dangerous primarily due to the lack of polyunsaturated fatty acids. Linoleic and linolenic acids are not synthesized in the human body, which is why they are called essential, 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 of true vitamins. In experiments on rats with vitamin F deficiency, growth retardation, dermatitis, and baldness with symptoms of hyperkeratosis were recorded. Fat-soluble vitamins A, D, E, K come with lipids in the body. With a deficiency of the latter, disturbances in growth, development, reproductive function, decreased resistance, etc. are observed. It should be noted that ruminant animals will not experience a deficiency of polyunsaturated fatty acids, which is associated with feeding characteristics and digestion. Plant foods contain many unsaturated acids.

2. Digestion and absorption of lipids, their disorders

Digestion of lipids 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 in the stomach under the action of gastric lipase, which is active at a neutral pH value (in adults it is inactive, since the pH of their gastric juice is 1.5 – 2.5). Subsequently, the breakdown of milk fats continues in the intestines 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 the enterocytes. Fat-soluble vitamins are also absorbed along with them.

In the cells of the mucous membrane of the small intestine, resynthesis of fats characteristic of this organism, as well as cholesterol esters and FLIP, occurs. From these components and proteins, lipoprotein complexes are formed - chylomicrons (CM). They are large in size, therefore, through exocytosis, they are first released into the chyle 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 transported to the liver.

The causes of impaired digestion and absorption of lipids can be various factors.

2. Impaired secretion of pancreatic juice with lipolytic enzymes.

3. Diarrhea and acceleration of intestinal motility

4. Damage to the intestinal epithelium by various poisons (moniodoacetate, heavy metal salts), infectious agents, antibiotics (neomycin).

5. Violation of nervous and endocrine regulation - decreased vagal activity, excess adrenaline, lack of adrenal hormone, thyroxine, weaken fat absorption. This is also caused by 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 of divalent alkaline earth cations (calcium, magnesium) in food and water, 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 lack of bile pigments. At the same time, due to the loss of fat-soluble vitamins and polyene fatty acids, hair loss, fur 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 encased in a protein shell formed by special transport proteins - apoproteins, which ensure the solubility of lipoproteins. In addition to chylomicrons (CM), 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. Fine separation 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. In this case, CM 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 are HDL, which contains the largest amount of proteins.

On the other hand, high LPL activity in the capillaries of adipose tissue promotes obesity. There is also evidence that during fasting it decreases, but the activity of muscle LPL increases.

4. Hyperlipemia

Hyperlipemia is an increase in fat content in the blood. Hyperlipemia can be nutritional, transport and retention.

Nutritional hyperlipemia occurs after eating fatty foods. Simultaneously with the increase in fat content in the blood, there may be an increase in the content of other substances from the lipid group (phospholipids, cholesterol). The total increase in these substances is called lipidemia. Nutritional hyperlipemia is most often characterized by a temporary increase in chylomicrons in the blood.

Transport hyperlipemia is associated with increased breakdown of fats and the release of free fatty acids (FFA) from the depot during fasting, stress, and diabetes. Lipolysis of adipose tissue and bone marrow is promoted by adrenaline, glucagon, thyroxine, somatotropin and adrenocorticotropic hormone. 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 the Latin retentio - to delay) develops due to a delay in the transition of neutral fats from the blood to the tissues. It may be due to insufficient concentration of albumins transporting FFA - in liver pathology (insufficient synthesis of albumins), in nephrotic syndrome (loss of protein 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 unit of lipostat is the hypothalamus, where the nuclei of the autonomic nervous system are located. In 1961, an Indian pathophysiologist established that the hunger center is located in the ventrolateral nuclei of the hypothalamus, and the satiety center (satiety) is in the ventromedial 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 mobilization of fat (i.e., its breakdown into glycerol and fatty acids) are active and constant, and they are most expressed in adipose tissue.

Adipose tissue is not inert, as it seems at first glance, but a metabolically very active formation, with constantly occurring processes of synthesis and breakdown of fats, proteins, and carbohydrates. Adipocytes - adipose tissue cells - are formed from fibroblasts. Adipocytes have many neurotransmitter and hormonal receptors on their surface (let us remember that adipose tissue is insulin dependent).

In a “fed” state, adipocytes secrete the peptide hormone leptin, which binds to leptin receptors in the ventromedial nuclei (satiety center). From the satiety center, inhibitory signals are sent to the hunger center, and hunger recedes. Also, under the influence of leptin, the production of neuropeptide Y decreases in the hunger center. Neuropeptide Y stimulates feeding behavior, the search and consumption of food by animals, and the production of insulin. Thus, initially the fat cell itself normally responds to saturation and sends leptin signals about this.

Lipogenesis activated after eating. The concentration of glucose in the blood increases, which stimulates insulin secretion. Under the influence 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 are converted 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 VLDL. VLDL delivers 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 and glucagon levels contributes to an increase in 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 quickly metabolized, carrying a large flow of energy. Lipolysis stops after food intake and insulin secretion.

Glucocorticoid hormones increase the mobilization of fat from adipose tissue. But this effect may be overshadowed by other effects of these hormones: the ability to cause hyperglycemia through gluconeogenesis and stimulate insulin secretion. And insulin, as already mentioned, stimulates lipogenesis.

The participation of the nervous system in the regulation of fat metabolism is confirmed by 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 irritated. Desympathization prevents the release of fat from the depot. Irritation of the parasympathetic nerves is accompanied by fat deposition.

6. Lipostat violation

Violation of the complex system of neurohumoral regulation underlies excess fat deposition in adipose tissue - obesity.

_Primary obesity develops when the caloric content of the diet exceeds the energy needs of the body. Recently, it has been believed that absolute or relative leptin deficiency plays a key role in the development of primary obesity.

Humans and animals have an “obesity gene” - obese gene (ob), which encodes leptin. As a result of a gene mutation, the amount of leptin in the blood decreases (absolute leptin deficiency). Low levels of leptin in the blood serve as a signal of insufficient fat reserves in the body. The hunger center continues to secrete 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 the leptin receptors in the hypothalamus. In this case, 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. Gaining excess weight is impossible without excess energy intake over its expenditure, therefore physical inactivity is a risk factor for the development of obesity.

Secondary obesity manifests itself as a syndrome with 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 to develop ketosis than animals of average fatness. In obese animals, the reproductive cycle is disrupted, and cows often remain infertile. Calves, lambs, piglets, and puppies from obese mothers are often born weakened and prone to diseases. 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, it is possible that exhaustion, characterized by a significant loss of body fat reserves. Exhaustion is observed with prolonged fasting, severe hyperpyretic fevers, type 1 diabetes, and emotional stress.

The lipolytic effect is strongly expressed in hyperthyroidism, with increased release of adrenaline and norepinephrine by the medulla of the adrenal glands, and chronic diseases. Cancer cachexia, which occurs due to intoxication, is well known. In addition, malignant cells are “traps” of glucose and other energy equivalents. In type 1 diabetes mellitus (hypoinsulinemia), the anabolic effects of insulin on lipids and proteins are lost. Therefore, exhaustion is an essential part of the clinical picture of insulin-dependent diabetes. Cachexia manifests itself in severe long-term lesions of the gastrointestinal tract associated with impaired absorption of substances.

7. Ketosis and liver steatosis

The central connection point of all metabolisms is acetyl coenzyme A. It is formed during the breakdown of glucose, glycerol, some amino acids, and β-oxidation of fatty acids. The bulk of ACoA is then oxidized in the tricarboxylic acid cycle to water and carbon dioxide, providing energy production. A sufficient amount of oxaloacetate is required for the involvement of ACoA in the TCA cycle. Another 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, acetotoacetic and β-hydroxybutyric acids. In monostriate animals and humans, the synthesis of ketone bodies occurs only in liver mitochondria. In monostriate animals, they can form in the mucous membrane of the proventriculus.

Ketone bodies can be used for energy needs by the brain, muscles, kidneys and lungs, especially under fasting conditions. During pregnancy, they are utilized by the placenta and fetus. Ketone bodies are normal metabolites that are quickly used, so their concentration in the blood is low (in humans 3 - 10 mg/dl, in large and small livestock up to 6 ml/dl).

During prolonged fasting, ketone bodies become the main source of energy for skeletal muscles, heart and kidneys, and 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 excess in the blood (ketonemia), then they appear in the urine (ketonuria), and in lactating animals in milk (ketonolactia) - the milk becomes bitter and unsuitable for use. This state is called ketosis. As a rule, acetone is removed with sweat, urine, and milk, which is not utilized by tissues. It is acetone that creates the peculiar fruity smell of an animal or person.

Hyperketonemia is dangerous for the body, as it leads to acidosis, first compensated, with a decrease in alkaline reserve, and then uncompensated, with a pH shift. The accumulation of protons in the blood disrupts the binding of oxygen by hemoglobin and the function of other proteins, including enzymes. Other metabolic disorders and signs of cardiovascular failure occur. Animals' appetite decreases or becomes distorted, weight is lost, productivity drops, and abortions often occur. With acidosis, bones lose calcium; the first signs of this are resorption of the caudal vertebrae and last ribs, and fragility of the horns. Hyperketonemia can lead to ketoacidotic coma.

The main link in the pathogenesis of ketosis is considered to be the accelerated breakdown of fats with the formation of ACoA against the background of a deficiency of carbohydrates or oxaloacetate for the TCA cycle.

Conventionally, primary and secondary ketosis are distinguished. 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 cows, sheep and goats with multiple pregnancies. Low-productive cattle, pigs, and 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 feeding concentrated feed rich in protein, cakes and other high-fat components, the digestion of cellulose by rumen microflora is inhibited, the proportion of volatile fatty acids (VFA) changes: butyric acid (ketogenic) accumulates to the detriment of propionic acid (antiketogenic). Glucose is synthesized from it through gluconeogenesis. Do not feed silage with a high content of butyric acid, rotten or 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 aggravated by the secretion of carbohydrates in milk: it is estimated that a cow secretes up to 2 kg of milk sugar during 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 are burned in the flames of carbohydrates.” How to understand this famous phrase? In order for ACoA to be oxidized in the TCA cycle, it needs to bind with 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 cycle. Excess ACoA is used to synthesize ketone bodies, a bypass energy supplier.

Knowledge of the pathogenesis of ketosis in ruminants allows the use of propionic acid and glucose as therapeutic and corrective drugs.

Secondary ketosis occurs in animals and humans as a result of a primary disease of any organ. Secondary ketosis can occur with general starvation, diabetes mellitus, debilitating fever, heavy muscle load, and liver pathologies.

Ketoacidosis reaches dangerous levels in diabetes mellitus; the concentration of ketone bodies in this disease can reach 400-500 mg/dl. Ketoacidotic coma is one of the causes of death in diabetes mellitus.

What is 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 into the liver. The liver undergoes final metabolism of the remains of cholesterol, LDL, HDL and secretes VLDL and HDL precursors. If the supply of lipids to the liver prevails over the rate of assembly and secretion of VLDL, then prolonged fat retention leads to steatosis and fatty liver (fatty hepatosis). The fat content in the liver then exceeds 8-10% of the dry matter mass. The same phenomena can be observed in other organs. Increased fat content in tissues (except adipose tissue) for a long time is called fatty infiltration. Disruption of the connection 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 displaces the nucleus to the periphery and displaces cytoplasmic organelles. This can lead to necrobiosis and then necrosis of hepatocytes. Activation of macrophages that carry out phagocytosis of necrotic cells can lead to fibrosis, and in severe cases, liver necrosis.

There are two main points in the development of fatty hepatitis: an increase in the supply of lipids and a decrease in their oxidation, especially fatty acids. An increase in the flow of lipids into 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, which reduce the activity of oxidative enzymes. This can be intoxication with bacterial poisons, chloroform, arsenic, phosphorus, carbon tetrachloride, nitrates, etc. Contributing factors are hypovitaminosis, hypoxia, acidosis, autoimmune processes.

Carnitine, a transmembrane mitochondrial shuttle, is required for the transfer of fatty acids and their oxidation in the mitochondria of hepatocytes. The assembly of VLDL, which carries endogenous fats, requires phospholipids containing choline. Both carnitine and choline require methyl groups. Consequently, all substances that are donors of methyl groups will promote the oxidation of fatty acids and the secretion of VLDL, which frees the liver of excess fat. Such substances are collectively called “lipotropic factors”. These, in addition to carnitine and choline, include methionine, betaine, vitamins B6 and B12.

Phospholipids (for example, lecithin) promote 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. It was called lipocaine. So far it has not been isolated 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, heart, and 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 final product of oxidative reactions is water, but so-called reactive oxygen species are also formed - hydroxyl radical, superoxide anion, hydrogen peroxide. They are capable of removing electrons from organic molecules, turning them into active radicals and thus triggering 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 self-destruction of organic molecules, including DNA. Lipid peroxidation (LPO) located in cell membranes can lead to cell death. Unsaturated fatty acids are most susceptible to the action of reactive oxygen species.

LPO destroys cells during atherosclerosis, tumor development, and nerve cells that contain a lot of lipids. The body has systems for protecting cells from reactive oxygen species: enzymes and vitamins with antioxidant effects. The enzyme superoxide dismutase (SOD) converts superoxide anions into hydrogen peroxide. The enzyme catalase 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 a coenzyme of glutathione peroxidase, so it, like vitamins E, C and β-carotenes, is classified as an antioxidant protection factor.

9. Eicosanoids

Eicosanoids are biologically active substances that are synthesized in many cells from polyunsaturated fatty acids containing 20 carbon atoms (the word “eicosis” 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 acid, 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. Activation of the enzyme can occur under the influence of many factors: histamine, cytokines, contact of the antigen-antibody complex with the cell surface, mechanical stress. 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 classified as cellular mediators of inflammation. Prostaglandins dilate arterioles, increase the permeability of the cell wall, which stimulates transudation 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), increased local temperature (calor), and pain (dolor). Pain occurs due to overstimulation of chemoreceptors by protons, histamine-like substances, as well as 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 triggering 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, promoting their spasm. This creates conditions for the formation of a blood clot and the prevention of bleeding in the area of vessel damage. Platelets are also activated when they encounter an atherosclerotic plaque. In this case, the formation of a blood clot 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 the coagulation and anticoagulation systems of the blood.

Synthetic analogues of prostaglandins find their use as medicines. For example, the ability of PG E2 and PG F2 to stimulate contraction of the uterine muscles is used to stimulate labor. PG E1 and PG F1, by blocking type II histamine receptors in the cells of the gastric mucosa, suppress the secretion of hydrochloric acid and thereby promote the healing of gastric and duodenal ulcers.

On the other hand, for inflammation, steroidal and non-steroidal (aspirin, ibuprofen, indomethacin) anti-inflammatory drugs are used. They inactivate enzymes that stimulate the formation of eicosanoids, mediators of inflammation. Steroid drugs have a much stronger anti-inflammatory effect than non-steroidal 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 - gruel, skleros - hard) - progressive changes mainly in the inner lining of arteries of the elastic and muscular-elastic type, consisting in excessive accumulation of lipid 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, and limbs. As a result of atherosclerotic lesions, the lumen of the arteries narrows, the blood supply to organs and tissues is disrupted, thrombosis, embolism, calcification, and aneurysms 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, 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 endothelial cells can be provoked 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 drugs there. In the vessel wall, LPs are isolated from the antioxidant factors of the blood plasma, and therefore are susceptible to changes by lipid peroxidation products. Macrophages phagocytose 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 resembling foam remain. This is the first stage of atherogenesis - the formation of a fatty (lipid) strip. But the deposition of lipids in the arterial wall does not necessarily indicate the transition of the process to the next stage - the formation of a fibrous plaque.

Fibrous plaque is called atheroma and fibroatheroma. First, atheroma is formed, characterized by a significant accumulation of foam cells, smooth muscle cells, lymphocytes, and platelets. SMCs migrate from the middle lining of the arteries under the influence of biologically active substances from macrophages and platelets - kinins, prostaglandins, chemotaxis factors, growth factors, etc. Under the influence of growth factors, 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 it, since the trapped LDL consists primarily of cholesterol. Gradually, the 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 and ulceration, which activates thrombosis. Complications of these processes are ischemia and organ infarctions. Violation of the integrity of the fibrous plaque leads to thinning of the vascular wall, hemorrhages and bleeding. In the aorta, dissection of its walls and the development of an aneurysm - protrusion - are often noted. Aneurysms can be very large. Aneurysms end in rupture of the aorta or the formation of a large blood clot.

Thus, lipids are one of the main components of the cell of the animal body. Lipids organize the work of each cell: they form a membrane through which all chemical signals, including hormonal ones, are perceived. Steroid hormones and many biologically active substances are of lipid origin. Adipose and nervous tissues are built mainly from lipids. When lipid metabolism is disturbed, dysregulatory pathologies develop in the form of ketosis, hepatic steatosis, atherosclerosis, obesity, etc.

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