Blood lipids are transported. Lipid transport

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. XM have quite big size, so after eating fatty foods they give blood plasma 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. At diabetes mellitus When insulin deficiency occurs, LPL levels decrease. As a result, it accumulates in the blood a large number of LP. 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). At successful treatment the underlying disease they disappear.
Hypolipoproteinemia includes the following conditions.
1. Abetalipoproteinemia occurs in 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, 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 level 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 nature: the content of cholesterol and VLDL is increased, the severity of the 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 insoluble in water, special transport forms are formed to transport them from the intestinal mucosa to organs and tissues: chylomicrons (CM), very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), high-density lipoproteins (HDL). Directly from the mucous membrane of the small intestine, transport of absorbed and resynthesized lipids occurs in the composition of chylomicrons. CM are protein-lipid complexes with a diameter of 100 to 500 nm, which, due to their relatively large size, cannot immediately penetrate into the blood. First, they enter the lymph and, as part of it, enter the thoracic lymphatic duct, and then into the superior vena cava and are carried throughout the body with the blood. Therefore, after eating a fatty meal, the blood plasma becomes cloudy within 2 to 8 hours. Chemical composition of HM: General content lipids – 97-98%; their composition is dominated by TAG (up to 90%), the content of cholesterol (C), its esters (EC) and phospholipids (PL) accounts for a total of -7-8%. The protein content that stabilizes the structure of chemical compounds is 2-3%. Thus, CM is a transport form of “dietary” or exogenous fat. The capillaries of various organs and tissues (fat, liver, lungs, etc.) contain lipoprotein lipase (LP-lipase), which breaks down TAG of chylomicrons into glycerol and fatty acids. In this case, the blood plasma becomes clear, i.e. ceases to be cloudy, which is why lipase lipase is called a “clearing factor.” It is activated by heparin, which is produced mast cells connective tissue in response to hyperlipidemia. TAG breakdown products diffuse into adipocytes, where they are deposited or supplied to other tissues to cover energy costs. In fat depots, as the body needs energy, TAG breaks down into glycerol and fatty acids, which, in combination with blood albumin, are transported to the peripheral cells of organs and tissues.

Remnant CMs (i.e., those remaining after TAG cleavage) enter hepatocytes and are used by them to build other transport forms of lipids: VLDL, LDL, HDL. Their composition is supplemented by TAG fatty acids, phospholipids, cholesterol, cholesterol esters, sphingosine-containing lipids synthesized in the liver “de novo”. The size of CMs and their chemical composition change as they move along the vascular bed. CMs have the lowest density compared to other lipoproteins (0.94) and the largest sizes (their diameter is ~ 100 nm). The higher the density of the LP particles, the smaller their size. The diameter of HDL is the smallest (10 - 15 nm), and the density ranges from 1.063 - 1.21.

VLDL are formed in the liver and contain 55% TAG, so they are considered a transport form of endogenous fat. VLDL transports TAG from liver cells to heart cells, skeletal muscles, lungs and other organs that have the lipid enzyme lipase on their surface.

LP - lipase breaks down VLDL TAG into glycerol and fatty acids, converting VLDL into LDL (VLDL - TAG = LDL). LDL can also be synthesized “de novo” in hepatocytes. Their composition is dominated by cholesterol (~ 50%), their function is the transport of cholesterol and phospholipids to the peripheral cells of organs and tissues, which have on their surface specific receptors to LDL. Cholesterol and phospholipids transported by LDL are used to build the membrane structures of peripheral cells. Absorbed by various cells, LDL carries information about the cholesterol content in the blood and determines the rate of its synthesis in cells. HDL is synthesized mainly in liver cells. These are the most stable forms of lipoproteins, because contain ~50% protein. They are characterized by a high phospholipid content (~20%) and a low TAG content (~3%). HDL (see Table No. 1) is synthesized by hepatocytes in the form of flat disks. Circulating in the blood, they absorb excess cholesterol from various cells, vessel walls and, returning to the liver, acquire spherical shape. THAT. , main biological function HDL transports cholesterol from peripheral cells to the liver. In the liver, excess cholesterol is converted into bile acids.

Table No. 1. Chemical composition of transport lipoproteins (%).

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 drugs are synthesized in the body; they differ in chemical composition and are formed in different places and transport lipids in various directions.

Medicines are separated using:

• 1) electrophoresis, by charge and size, on b-LP, v-LP, pre-c-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. During the post-absorptive period and during fasting, only LDL and HDL are present in the blood.

Main types of lipoproteins

Composition, % VLDL CM

• (pre-in-LP) DILI
• (pre-in-LP) LDL
• (v-LP) HDL
• (b-LP)

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 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. Apoproteins can be peripheral (hydrophilic: A-II, C-II, E) and integral (have a hydrophobic region: 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 XM

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 the hydrolysis of TG in the LP Liver HDL > CM, VLDL

D Cholesteryl ester transfer (CET) Liver HDL

E Receptor, phagocytosis LP liver HDL > CM, VLDL, LDLP

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 the endothelial cells of the capillaries of blood vessels. It hydrolyzes TG in the composition of the drug to glycerol and 3 fatty acids. With the loss of TG, CM turn into residual CM, 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 interacts with the proteins ano B-100 and apo E, binds LDL well, worse than DILI, VLDL, and residual CM containing these apos. Tissue cells contain a large number of LDL receptors on their surface. For example, one fibroblast cell has from 20,000 to 50,000 receptors.

If the amount of cholesterol entering a cell exceeds its need, then the synthesis of LDL receptors is suppressed, which reduces the flow of cholesterol from the blood into the cells. When the concentration of free cholesterol in the cell decreases, on the contrary, the synthesis of HMG-CoA reductase and LDL receptors is activated. Hormones stimulate the synthesis of LDL receptors: insulin and triiodothyronine (T3), sex hormones, and glucocorticoids reduce it.

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 by endocytosis of lipoproteins, a certain amount of cholesterol enters cells by diffusion from LDL and other lipoproteins upon their contact with cell membranes.

The normal concentration in the blood is:

• * LDL
• * total lipids 4-8g/l,
• * TG 0.5-2.1 mmol/l,
• * Free fatty acids 400-800 µmol/l

Lipids are water-insoluble compounds, so their transport in the blood requires special water-soluble carriers. Such transport forms are blood plasma lipoproteins, which belong to free lipoproteins (LP). Resynthesized fat in intestinal cells, or synthesized fat in the cells of other organs and tissues, can be transported by blood only after inclusion in the drug, where proteins play the role of a stabilizer.

LP micelles have an outer layer and a core. The outer layer consists of protein, PL and free cholesterol, which have hydrophilic polar groups and exhibit an affinity for water. The core is formed from TG and CS esters. All these compounds included in the core do not have hydrophilic groups.

LPs transport: PL, TG, cholesterol. Can transport some fat-soluble vitamins (A, D, E, K). There are 4 classes of transport drugs, which differ from each other in chemical composition, micelle size and transported lipids. Since they have different densities and settling rates in NaCl solution, they are divided into the following groups:

HM – chylomicrons. They form in the wall thin section intestines;

VLDL - very low density lipoproteins - are formed in the intestinal wall and liver;

LDL - low-density lipoproteins - are formed in the intestinal wall, liver and capillary endothelium from VLDL under the action of lipoprotein lipase;

HDL - high-density lipoproteins - are formed in the wall of the small intestine and liver.

Thus, blood lipids are formed and secreted by 2 types of cells - enterocytes and hepatocytes. During electrophoresis of blood serum proteins, LPs move in the zone of a- and b-globulins, therefore, based on their electrophoretic mobility, they can be designated as:

VLDL – pre-b-LP

LDL – b-LP

HDL – a-LP

XM - as the largest particles in size and the heaviest, do not move during electrophoresis and remain at the start.

It is generally accepted that CMs are absent in the blood on an empty stomach, and they are synthesized in the wall of the small intestine especially actively after eating a fatty meal. They transport mainly TG from intestinal cells and fat depots to the cells of organs and tissues. Have big sizes micelles and therefore do not penetrate the walls of blood vessels. The breakdown of CM is completed 10-12 hours after eating under the influence of liver lipoprotein lipase, adipose tissue, and capillary endothelium. Hydrolysis products are involved in cellular metabolism.

VLDL and LDL transport predominantly cholesterol. These fractions bring it into the cells of organs and tissues that use cholesterol to build biomembranes and form steroid hormones and vitamins of group D. They are also called atherogenic fractions (pre-b and b).

HDL transports cholesterol from cells and tissues to the liver, where it is oxidized, turning into bile acids. This antiatherogenic fraction.

VLDL, LDL and HDL are absorbed by endocytosis into the cells of the liver, intestines, kidneys, adrenal glands, and adipose tissue and are destroyed in lysosomes or microsomes.

Resynthesized fat in the intestinal wall combines with a small amount of protein and forms stable complex particles called XM. Since the particle sizes are large, they cannot penetrate from the endothelium of intestinal cells into the blood capillaries. They diffuse into the lymphatic system of the intestine, and from it into the thoracic duct and into the bloodstream. Already after eating, 1.5-2 hours later, terminal CMs begin to grow, which reach a maximum 4-6 hours after eating fatty foods.

Active entry of CM into the liver and adipose tissue, where, under the influence of lipoprotein lipase enzymes (regulated by heparin), they break down with the formation of glycerol and IVH. Part of the IVH is used by cells, and part by transport proteins in the blood. The decay of CM is completed 10-12 hours after eating.

Atherogenic index– the ratio of cholesterol in VLDL, LDL and HDL.

TO ater= (ХСлпнп + ХСлпнп) / ХСлппп. Normally, the atherogenic index is 2-3, but if it is above 4, then the likelihood of developing atherosclerosis is very high.

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 fluctuates different types 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.