CHOLESTERIC EXCHANGE (Greek
chole bile + stereos firm) — set of reactions of biosynthesis of cholesterol (see) and its disintegration in a human body and animals. In a human body per day apprx. 500 mg of cholesterol is oxidized in bile acids, approximately the same amount of sterols is excreted with excrements, apprx. 100 mg a small amount of cholesterol is allocated with skin fat (apprx. 40 mg) used for formation of kortikoidny and sex hormones, and also D3 vitamin, 1 — 2 mg of cholesterol is removed with urine. At the feeding women with breast milk 100 — 200 mg of cholesterol a day are allocated. These losses are made up due to synthesis of cholesterol in an organism (at the adult in days apprx. 700 — 1000 mg) and receipts it with food (300 — 500leg). Chastyshshchevy cholesterol, and also a part of the cholesterol which came to a gleam of intestines with bile is soaked up in a small bowel in the form of fatty micelles (see. Fatty exchange). Ethers of cholesterol are hydrolyzed previously at action of a holesterinesteraza (see) pancreatic and intestinal juice. In a wall of a small bowel cholesterol is used for formation of chylomicrons (see Lipoproteids), in structure to-rykh it comes at first in limf, system, and then to a blood channel.
In capillaries fatty and nek-ry other fabrics as a result of impact on chylomicrons a lipoproteid lipase the particles enriched with ethers of cholesterol and phospholipids, which received the name of remnantny (residual) particles are formed. These particles are late in a liver where they are exposed to disintegration. The cholesterol released at the same time along with the cholesterol synthesized in a liver forms a so-called common pool of hepatic cholesterol, to-ry is used as required for formation of lipoproteids (see).
It is established that at the person and nek-ry animals lipoproteids of low density transport cholesterol in bodies and fabrics, and capture of lipoiroteidny particles cells of these bodies and fabrics it is carried out with the participation of specific receptors. Cholesterol whether-poproteidnykh delivered in a cell in structure of particles, goes on a covering of requirements of a cell (formation of membranes at cell division, synthesis of steroid hormones, etc.). An excess part of neeterifi-tsirovanny (free) cholesterol turns into its ethers at effect of the enzyme which is contained in a cell — cholesterol-atsiltransfe-times (KF 184.108.40.206). The return transport of not esterified cholesterol from various bodies and fabrics in a liver is carried out by lipoproteids of high density, and in a blood channel there is etherification of the taken cholesterol with the participation of lecithin p enzyme cholesterol-lecithin - acyltransferases (KF 220.127.116.11). The cholesterol delivered in such way to a liver goes on formation of bile acids (see).
Synthesis of cholesterol is carried out in cells of almost all bodies p fabrics, however in significant amounts it is formed in pechenp (80%), a wall of a small bowel (10%) and skin (5%). K. Bloch, F. Linen, etc. showed the main reactions of biosynthesis of cholesterol (they are not less than 30). Complex process of biosynthesis of cholesterol can be divided into three stages: 1) biosynthesis mevalono-howl acids; 2) formation of squalene from mevalonovy acid; 3) cyclization of squalene and formation of cholesterol (see the scheme).
Consider that the main source of education mevalonovy to - you in a liver are atsetil-KOA, and in muscular tissue — a leucine. And p another connections as a result of a number of euzymatic reactions form that r-gidroksi-r-metilglutaril-KOA (GMG-KOA) which then is recovered in mevalonovy to - that. Recently it is shown that in synthesis mevalonovy to - you in a liver can join and malonil-KOA.
The reaction determining the speed of biosynthesis of cholesterol in general is recovery GMG-KOA in mevalonovy to - that; this process catalyzes NADF-H2-dependent enzyme GMG-KOA-reduktaza (KF 18.104.22.168). This enzyme is subject to influences from a number of factors. So, activity of GMG-KOA-reduktazy increases (or contents it increases in a liver) and the speed of synthesis of cholesterol in general increases at action of ionizing radiation, administration of thyroid hormones, surfactants, a holestira-mine, and also at a hypophysectomy. Oppression of synthesis of cholesterol is noted at starvation, a thyroidectomy and at receipt in an organism of food cholesterol. The last oppresses activity (or synthesis) enzyme of GMG-KOA-reduktazy.
Synthesis of cholesterol in a wall of a small bowel is regulated only by concentration of bile acids. So, absence in intestines in the presence of outside bilious fistula leads them to increase in synthesis of cholesterol in a small bowel by 5 — 10 times.
At the second stage of synthesis there is a phosphorylation mevalono-howl to - you with the participation of ATP and education of several fosforilirovanny intermediate products (see Phosphorylation). At decarboxylation of one of them the izopentenil-pyrophosphate is formed, a part to-rogo turns in dimethyl a llil-pyrophosphate. Vzaimodey
leads a stviye of these two connections to education a dimeasure — the gera-Nile-pyrophosphate containing 10 carbon atoms. Geranyls-pirofoses-veils it is condensed with a new molecule of an izopentenil-pyrophosphate and forms the trimmer — the farnezil-pyro-phosphate containing 15 carbon atoms. This reaction goes with eliminating of a molecule of a pyrophosphate. Then two molecules of a farnezil-pyrophosphate are condensed, losing everyone the pyrophosphate, and form hexamer the squalene containing 30 carbon atoms.
The third stage of synthesis includes the oxidizing cyclization of squalene which is followed by migration of double bonds and formation of the first cyclic connection — la-nosterina. Lanosterin already has hydroxylic group in
situation 3 and three superfluous (in comparison with cholesterol) methyl groups. Further transformation of a lanoste-rin can be made in two ways, and both in that and in other case intermediate products are connections of the sterinovy nature. It is taken in about the 24th way, 25-digidrolanosterin and some other sterols, including 7 dihydrocholesterol serving by the direct predecessor of cholesterol more for granted. Other possible way — transformation of a lanosterin into a zymosterol, and then in desmosterin, from to-rogo at recovery is formed cholesterol.
If to sum up the general result of all reactions of biosynthesis of cholesterol, then it can be presented in the following form:
18CH3CO-S-KoA + 10 (N +) + V202 —
— C2:H460 + 9C02 + I8K0A-SH. A source of carbon of cholesterol is atsetil-KOA (and the leucine can also be it malonil-KOA), a source of hydrogen — water and niacinamide denindinukleotidfosfat, and a source of oxygen — molecular oxygen.
Since squalene and finishing cholesterol all intermediate products of biosynthesis are insoluble in an aqueous medium therefore they participate in end reactions of biosynthesis of cholesterol in connected about squalene - or sterinperenosyashchy proteins a state. It allows them to be dissolved in cytoplasm of a cell and creates conditions for course of the corresponding reactions. The cholesterol-transferring protein provides also movement of sterols in a cell that is important for its entry into a cell membrane, and also for transport in the cellular systems which are carrying out a catabolism of cholesterol.
The catabolism of cholesterol proceeds in a liver (its oxidation in bile acids), in adrenal glands and a placenta (education from cholesterol of steroid hormones), in testicular fabric and ovaries (formation of sex hormones). At biosynthesis of cholesterol in skin on a closing stage a small amount of a 7-degidrokholesterin is formed. Under the influence of UV rays it turns into D3 vitamin.
Peculiar transformations are undergone by cholesterol in a large intestine. It is about that part of the food cholesterol or cholesterol which came to intestines with bile, edges did not undergo absorption. Under the influence of microbic flora of a large intestine there is a recovery of cholesterol and formation of so-called neutral sterols. Their chief representative is coprosterol. The pilot studies conducted with use of tracer and other techniques showed that the speed of updating of cholesterol in various bodies and fabrics is not identical; it is highest in adrenal glands and a liver and is extremely low in a brain of mature animals.
Pathology of cholesteric exchange. Disturbances of X. lakes are usually connected with an imbalance between amount of the cholesterol synthesized in an organism and arriving with food, on the one hand, and amount of the cholesterol which is exposed to a catabolism — with another. These disturbances are shown in change of level of cholesterol in a blood plasma, to-rye are classified as a hypercholesterolemia or a hypochilesterinemia (for adult population of the advanced countries of size over 270 mg / 100 by ml and lower than 150 mgtso0 in ml respectively).
The hypercholesterolemia can be primary (hereditary or alimentary) and secondary, caused by various diseases. The hereditary (family) hypercholesterolemia is characterized by a high level of cholesterol and lipoproteids of low density (LPNGL in a blood plasma. At a homozygous hypercholesterolemia the level of a cholesterinemia can reach 700 — 800 mg! 100 ml, and at heterozygous — 300 — 500 л^г/100 ml. A hereditary hypercholesterolemia genetically caused absence (at homozygotes) or a shortcoming (at heterozygotes) is the cornerstone of specific receptors to lipoproteids of low density at cells owing to what capture and the subsequent catabolism of these lipoproteids rich with cholesterol cells of parenchymatous bodies and fabrics sharply decreases. As a result of the lowered capture and decrease in a catabolism of lipoproteids of low density the hypercholesterolemia develops (see). The last leads to a prematurity of atherosclerosis (see) and its clinical manifestations — coronary heart disease (see), passing ischemia of a brain (see the Stroke), etc. Especially hard atherosclerosis at a homozygous form proceeds; at such patients the xanthomatosis (see), a lipoid arch of a cornea (adjournment of cholesterol in a cornea of eyes), a myocardial infarction at youthful age is often observed.
Prevalence of a homozygous form of a hypercholesterolemia is small (about one case on 1 million inhabitants). The heterozygous form — one case on 500 inhabitants meets more often.
And the l of an iment of a rn I gip ER x about l of the EU that r in-
an emiya is characterized by the increased level of cholesterol in a blood plasma owing to long consumption of large numbers of the food rich with cholesterol (chicken yolks, caviar, liver, animal fats, etc.). The alimentary hypercholesterolemia of this or that degree of manifestation is characteristic of residents of the advanced industrial countries. According to population researches there is a direct dependence between the level of cholesterol in blood and prevalence of coronary heart disease.
In an experiment on various animals (rabbits, Guinea pigs, monkeys) it is shown that introduction of massive doses of cholesterol with food leads to sharply expressed hypercholesterolemia and bystry development of atherosclerosis. The pilot models of a hypercholesterolemia and atherosclerosis for the first time offered H. N. Anichkov and S. S. Hala-tov (1913), are widely used in scientific research.
The secondary hypercholesterolemia meets at a hypothyroidism (see), a diabetes mellitus (see a diabetes mellitus), a nephrotic syndrome (see), gout (see), etc. and quite often is followed by development of atherosclerosis (see the Hypercholesterolemia).
Allocate primary and secondary hypochilesterinemia. Primary hypochilesterinemia is characteristic of a hereditary disease — an abe-pgalipoproteinemiya (see). At this disease almost total absence in a blood plasma of lipoproteids of low density (at homozygotes) or their considerable decrease is noted (at heterozygotes). Level of the general cholesterol does not exceed 75 mg! 100 ml. The homozygous form of a disease proceeds exclusively hard. Genetically caused disturbance of synthesis of apoprotein B — the main protein of lipoproteids of low density is the cornerstone of an abetalipoproteinemiya.
Secondary hypochilesterinemias are observed at a cachexia, a hyper-thyroidism, an addisonovy disease and parenchymatous diseases of a liver, at a number of infectious diseases and intoxications (see the Hypochilesterinemia). At insufficient activity in a plazkhma of blood of enzyme lecithin - cholesterol - acyltransferases, or JIXAT (hereditary L the X AT-insufficiency), cholesterol of plasma, responsible for etherification, is observed accumulation not - esterified cholesterol in membranes of erythrocytes and cells of kidneys, a liver, a spleen, marrow, a cornea of an eye. Sharply the share of esterified cholesterol in a blood plasma decreases and at the same time level not - esterified cholesterol and lecithin increases. Patients from hereditary JlXAT-nedostatochnostyo have walls of arteries and capillaries are subject to destructive changes that is connected with adjournment of lipids in them. The heaviest changes happen in vessels of renal balls that leads to development of a renal failure (see).
One of widespread disturbances of X. the lake is formation of gallstones, the main component to-rykh is cholesterol (see Cholelithiasis). Formation of gallstones happens owing to crystallizing out of cholesterol at its rather high concentration in bile and rather low concentration in it bilious to - the t and phospholipids having ability to dissolve cholesterol. Researches showed that there is a feedforward between the level of cholesterol in a blood plasma and prevalence of a cholesterosis (see) and cholelithiasis.
Bibliography: Klimov A. N, and N and -
N. G kulcheva. Lipoproteids, dis-lipoproteidemiya and atherosclerosis, L., 1984; Polyakova E. D. Ways of biosynthesis of cholesterol in a liver and their regulation, in book: Lipids, structure,
biosynthesis, transformations and functions, under the editorship of S.E. Severin, page 131, M., 1977;
it, Regulation of content of cholesterol in a cell, in book: Biochemistry of lipids and their role in a metabolism, under the editorship of
S.E. Severin, page 120, M., 1981; Fina-g and L. K N. Exchange of cholesterol and its regulation, Kiev, 1980; Lipids and lipidoses, ed. by G. Schettler, B. — Heidelberg, 1967; Sodhi H. S., Kudchod-k a r B. J. a. Mason D. T. Clinical methods in study of cholesterol metabolism, Basel a. o., 1979. A. H. Klimov,