Muscle structure. The main components of contractile systems. Muscles make up about half of the total mass
bodies.
The main dynamic function of muscles is to provide
mobility by contraction and subsequent
relaxation. A muscle cell is made up of
individual fibers. The cell contains myofibrils
– organized bundles of proteins located
along the cell. Myofibrils are made from
filaments - protein threads of two types - thick
and thin filaments. The main protein of fat
filaments are myosin, thin filaments are actin.
The functional unit of the myofibril is the sarcomere,
area of ​​myofibril between two Z plates.

Muscle structure. The main components of contractile systems.

The sarcomere includes a bundle of myosin filaments,
bundles attached to the M-plate (M-line) in the middle
actin filaments are attached to the Z-plate.
Muscle contraction is the result of shortening each
sarcomere, by pushing actin filaments between
myosin in the direction of the M-line. Maximum
shortening is achieved when the Z-plates
approach close to the ends of the little finger threads.
Z
M
Z

Reduction mechanism

Myosin - a protein of myosin filaments containing two
identical chains twisted together, N ends
have a globular shape, forming molecular heads.
These heads have a high affinity for ATP and
have catalytic activity -
catalyze the breakdown of ATP.
Actin in thin filaments is associated with protein
troponin, which has Ca++-binding
centers. Actin is a site that binds to myosin.
Muscle contraction is caused by an action potential
nerve fiber and occurs due to the energy of ATP.
The action potential causes the influx of Ca++ from
reticulum into the cytosol of the cell.

Mechanism of muscle contraction

Ca++
A
A. Ca++ binds to troponin
actin filaments and the actin center opens
binding to myosin; Myosin bound to ATP
B
B. Coupling of actin and myosin
threads, and the ATPase center is activated
myosin, the myosin head catalyzes
ATP hydrolysis;
IN
B. ADP and P leave the myosin head, this
leads to a change in its conformation and it
turns to line M, carrying
promotion and actin. Happening
reduction.
G
D. A new molecule attaches to myosin
ATP and the connection between the threads is disrupted.
Hundreds of myosin molecules work
simultaneously promoting the actin filament

Muscle contraction. Conditions.

The force of contraction depends on the amount of myosin
heads included in the work, and therefore from
number of ATP molecules.
A resting muscle is elastic. Myosin head
bound to ATP.
The contracted muscle is inelastic and tense.
Stretch is prevented by the connection between actin and
myosin.
Rigidity occurs when there is a strong decrease in
ATP concentrations (hypoxia conditions). In these
conditions, a large number of myosin heads
remains associated with actin, because to exit
This state requires the addition of ATP to
myosin.

Sources of energy (ATP) for muscle contraction.

A muscle working with maximum activity consumes
energy is hundreds of times greater than at rest, and the transition from
from rest to work occurs in a fraction of a second. Due to this
muscles, unlike other organs, require mechanisms
changes in the rate of ATP synthesis over a very wide range
(excluding heart muscle).
The total ATP content in the muscles is only enough for 1 second of work.
1st stage of energy generation:
At the moment of training, the muscles experience a deficit
O2, and consequently, restriction of tissue respiration and
oxidative phosphorylation. The source of ATP in
the moment of activation is creatine phosphate.
This is the fastest way to generate energy.
The content of creatine phosphate in muscles is 3-8 times
more than ATP, this quantity ensures work in
for 3-5 seconds.

Sources of energy for muscle contraction

Creatine phosphate is formed from creatine and ATP. Creatine tripeptide is synthesized in the liver from glycine,
arginine and methionine.
Creatine R + ADP
creatine +ATP
The reaction is catalyzed by creatine kinase
Creatine phosphate, unused, non-enzymatic
turns into creatinine
Stage 2 of energy generation: another mechanism is activated:
Adenylate kinase reaction: ADP+ADP
ATP+AMP
Stage 3 of energy generation: mobilization accelerates
glycogen, anaerobic glycolysis is accelerated, and AMP
is an activator of phosphofructokinase
glycolysis. Substrate phosphorylation.
Stage 4: aerobic oxidation of carbohydrates, with prolonged
work fats. Oxidative phosphorylation.
Cardiac muscle is aerobic. IVF (70%).carbohydrates, PC

Creatine, creatinine. Diagnostic value.

norm
Liver
Gli
Arg
muscle dystrophy
Muscles
Muscles
Creatine
creatine
Meth
gly
arg
Creatine R
Creatinine
urine
The daily excretion of creatinine is a constant value - directly
proportional to mass.
There is no creatine in urine
Liver
Liver
Muscles
Muscles
Creatine
creatine
Creatine R
meth
Creatine
Creatinine
urine (creatinuria) urine
Creatine is not phosphorylated in muscles,
blood levels rise. Creatinine in
is not reabsorbed by the kidneys, so it
amount in urine reflects the amount
glomerular filtration.

Functional biochemistry of the liver

The liver occupies a central place in metabolism
substances, which is determined by the originality
topography and blood supply
The liver is an “altruist” organ. On the one hand, in
the liver synthesizes the necessary substances for
other organs - proteins, phospholipids, carnitine,
creatine, ketone bodies, cholesterol, glucose. WITH
on the other hand, provides protection to organs from
toxic substances formed in them,
foreign compounds and microorganisms.
The liver performs the following biochemical functions:
1. metabolic and homeostatic;
2. biliary and excretory
3. depositing (depot of fat-soluble vitamins);
4. neutralizing - detoxifying

Metabolic and homeostatic function

The performance of this function is due to the participation
liver in the metabolism of carbohydrates, lipids, proteins,
pigment metabolism, hemostasis.
The liver provides synthesis and entry into
blood of necessary compounds, their
transformation, neutralization, elimination,
ensuring homeostasis.
The role of the liver in carbohydrate metabolism:
In the liver, glucose is metabolized along all pathways: glycogen synthesis and mobilization, PPP, gluconeogenesis.
The role of the liver in carbohydrate metabolism is primarily
turn in ensuring normoglycemia, due to
organ-specific enzyme -
glucose-6-phosphatase.

The role of the liver in lipid metabolism

The liver is involved in all stages of lipid metabolism, including
digestion and absorption of hydrophobic products
digestion (bile is a secretion of the liver).
During the absorption period, the synthesis of IVF is accelerated in the liver,
which are used for the synthesis of TAG and PL. FL,
synthesized in the liver (and for export) are necessary for everyone
tissues, primarily to build membranes.
During fasting – beta-oxidation; for oxidation
Carnitine is needed, which is synthesized in the liver.
During fasting, ketone bodies are formed in the liver,
used as a source of extrahepatic
fabrics.
Cholesterol synthesis and its redistribution between
bodies due to the formation of transport forms -
VLDL and HDL. Formation from biliary cholesterol
acids

The role of the liver in protein metabolism.

About half of the body's proteins are synthesized in the liver, both for
own needs, and secreted:
- Blood plasma proteins - globulins and all albumins;
- Clotting factors – fibrinogen and vitamin K-dependent,
factors of the fibrinolysis system;
- group of transport proteins – cerulloplasmin (Cu++)
haptoglobin, transferrin, iron depot – ferritin;
- LP apoproteins;
- acute phase proteins – “C”-reactive, α1-antitrypsin, α2macroglobulin (for inflammation)
- -creatine.
- synthesis of non-essential amino acids;
- non-protein nitrogenous compounds – nitrogenous bases,
porphyrins, urea, uric acid
- In this regard, amino acid metabolism is active, enzymes are active
transamination – ALT and AST, deamination –
glutamate dehydrogenase.
Disturbance of protein synthesizing function manifests itself
changes in protein ratio – dysproteinemia.
Participation of the liver in pigment metabolism - in the formation
glucuronides and their excretion.

Bile formation and excretory function.

The liver produces bile acids from cholesterol
under the action of the enzyme 7α-cholesterol hydroxylase.
Enzyme activity is reduced by bile acids.
About 600 mg per day, here are the primary acids -
cholic and deoxycholic acids are conjugated with taurine and
glycocol, forming tauroglycocholic acids.
Excretion of bile acids main route of excretion
cholesterol
Excretory function is related to the structure of the liver. U
of each hepatocyte one side faces the bile
duct, the other to the blood capillary.
From the liver, various substances of endo- and exo-origin are excreted with bile through
intestines, or through the blood through the kidneys. Violation of this
functions affects lipid metabolism, accumulation in
the body of toxic products.

Detoxifying function of the liver.

In the body, during the process of life, they are formed
toxic metabolites as their own compounds,
and alien - xenobiotics. These connections may
be hydrophilic and hydrophobic.
An example of the neutralization of toxic products is
urea synthesis.
Hydrophobic, capable of being deposited in cells and
adversely affect the structure and metabolism in
cell, they must be inactivated.
The liver is a unique organ that contains mechanisms
neutralization (inactivation, detoxification) of such
connections. The mechanism of inactivation of such compounds
built according to a general scheme.
Inactivation can consist of two stages:
modifications and conjugations.

Chemical modification stage

The chemical modification stage provides
increasing the hydrophilicity of the substance and is required
for all hydrophobic compounds.
Increased hydrophilicity is ensured
numerous reactions -
hydroxylation, oxidation,
reduction, hydrolysis. In most cases
step begins with the hydroxylation reaction
enzymes of membranes of smooth reticulum of cells -
monooxygenases. The process is called
microsomal oxidation.
Monooxygenases are presented as
electron transport chain, central enzyme -
hemeprotein - cytochrome P450 has two centers
binding - with the oxidized substance and O2. And
has broad substrate specificity.
The source of hydrogen is NADPH PPP

Microsomal oxidation

O2
2H+ê
NADPH+
FAD(FMN) reductase
ê
ê
cytochrome
P450
Fe+2
2H+
SH
SOH
Fe+3
H2O
There are about 1000 cytochrome isoforms with varying specificities
Cytochrome P450 includes one oxygen atom in the substrate
(hydroxylates), the other reduces into water.
The appearance of hydrophilic properties in the substrate determines
possibility of 2 stages of inactivation

Conjugation stage

Conjugation with hydrophilic molecules:
UDP-glucuronic acid,
phosphoadenosine phosphosulfate (FAPS), etc.
Examples: formation of bilirubin glucuronide,
neutralization of the products of decay of gastrointestinal proteins.
The reactions are catalyzed by transferases.
Conjugation reduces reactivity
substances - their toxicity, increases
hydrophilicity, which means excretion from the body.
Not all substances undergo these two inactivations. This
depends on the structure (on the degree of hydrophilicity
toxic substance).

Indicators of liver dysfunction

With various liver diseases, its functions are all impaired
or some. Indicators of these violations are changes
blood levels of compounds or enzyme activity
coming from the liver.
There are a number of tests called functional tests.
liver tests:
Determination of enzyme activity ALT, AST
(de Ritisse coefficient), Fraction ratio
proteins – to identify dysproteinemia – sediment
thymol, Veltman tests; Definition
fibrinogen content; prothrombin
Determination of bilirubin and its types;
Determination of urea content;
Cholesterol determination and lipid ratio
Determination of the activity of gammaglutamyl transpeptidase enzymes; alkaline phosphatase
(cholestasis);

FUNCTIONAL BIOCHEMISTRY
To perform all necessary vital functions, the human body contains more than 200 types of specialized cells. A complex of morphologically similar cells that perform specific functions is called tissue. Tissues are morphologically formed into organs - formations with specific functions in a complex biological system, such as an organism.

Functional biochemistry clarifies the connections between the structure of chemical compounds and the processes of their mutual changes, on the one hand, and the function of subcellular particles, specialized cells, tissues or organs that include the mentioned substances, on the other.

Molecular defects lead to biochemical changes that clinically manifest themselves as diseases in which normal biochemical parameters of diagnostic value change. Knowledge of the basic biochemistry of the natural life processes of individual organs is necessary for a physician to identify violations of chemical processes, with their subsequent elimination or correction.

BIOCHEMISTRY OF THE LIVER

Liver- the central biochemical laboratory of the body, in which various metabolic transformations of substances occur. It is also involved in all metabolic processes occurring in peripheral tissues. Chemical composition of the liver: water - 70%, proteins - 12-24, lipids - 2-6, carbohydrates - 2-8, cholesterol - 0.3-0.5, iron - 0.02% and other minerals. In an adult healthy person, the liver weight averages 1-1.5 kg. Cellular composition of the liver:

1) hepatocytes - 80%, located in two layers and in contact with bile on one side, and with blood on the other;

2) endothelial cells - 15%;

3) connective tissue cells - 5%.

The peculiarity of the blood supply to the liver is that mixed blood (venous-arterial) circulates in it through sinusoids (dilated capillaries). 70-80% of the total blood volume enters it through the portal vein (venous blood) from the intestine, and along with this blood, the breakdown products of proteins, lipids, polysaccharides and nucleic acids arrive: glucose, amino acids, nitrogenous bases, chylomicrons, etc. 30 % of the blood is delivered to the liver by the hepatic artery (arterial blood), and along with it metabolites of peripheral tissues and organs are delivered: alanine, lactate, glutamine, HDL (mature), glycerol, oxygen in the form of the potassium salt of oxyhemoglobin, etc. The hepatic vein carries it out of the liver into the general bloodstream glucose, amino acids, blood plasma proteins, enzymes, ketone bodies, VLDL, HDL precursors, urea and a number of other substances.

The functions of the liver are numerous and complex, but the most important of them are biosynthetic, regulatory-homeostatic, hemostatic, urea-forming and bile-forming, excretory, catabolic, and detoxifying.

The most important function of the liver is biosynthetic. The following substances are synthesized in the liver: ketone bodies, glucose, cholesterol, cholesterol esters, plasma proteins, proteins of coagulation and anticoagulation systems, non-essential amino acids, IVH, PL, TAG (2nd resynthesis), VLDL, HDL precursors, biologically active peptides, gluconeogenesis enzymes, ornithine cycle enzymes, LCAT, heme, choline, creatine.

Some of the metabolites formed in the liver (glucose, cholesterol, ketone bodies, plasma proteins, etc.) are transported further into the cells of other organs and tissues (i.e. “for export”), where they are used for energy and structural purposes, and some are deposited stored (for example, glycogen, iron, fat-soluble vitamins) or excreted from the body if not used. One of the functions of the liver is excretory. The liver secretes cholesterol, bile acids, bile pigments, iron, and other substances into the lumen of the gastrointestinal tract. In maintaining the constancy of the internal environment of the body (homeostatic function), the role of the liver is unique, since it is the center of regulation of the main metabolic pathways: proteins, carbohydrates, lipids, nucleic acids and nucleotides, vitamins, water and electrolytes.

Features of the metabolism of amino acids, proteins and other nitrogen-containing substances in the liver

The liver plays a central role in maintaining nitrogen balance in the body, as it regulates the processes of utilization of nitrogenous substances and the release of their metabolites from the body. The main anabolic and catabolic processes of amino acids (transamination, deamination, decarboxylation) take place in the liver. Only in the liver are proteins of the coagulation system (prothrombin, fibrinogen, proconvertin, proaccelerin) and anticoagulation system (except plasminogen) synthesized. Liver, ceruloplasmin, transferrin, angiotensinogen. The liver provides, through the blood, other organs with a balanced mixture of essential and non-essential amino acids necessary for the biosynthesis of their own proteins. The liver synthesizes many nitrogen-containing substances of a non-protein nature (creatine, choline, uric acid, indican, heme, etc.), biologically active peptides (glutathione, carnosine, anserine), and the biosynthesis and breakdown of purine and pyrimidine nitrogenous bases also occurs. Only in the liver does the formation of urea occur - the main way of neutralizing ammonia in the body.

Features of carbohydrate metabolism in the liver

The following metabolic processes of carbohydrate metabolism take place in the liver: biosynthesis and breakdown of glycogen, necessary to maintain a constant concentration of glucose in the blood: gluconeogenesis, aerobic glycolysis, pentose phosphate pathway, fructose and galactose metabolism, Cori cycle, conversion of glucose into IVH, biosynthesis of heteropolysaccharides. The liver is the main organ supplying free glucose to the blood, since the liver hepatocytes contain the enzyme glucose-6-phosphatase, which breaks down glucose-6-phosphate into free glucose.

Features of lipid metabolism in the liver

Lipid metabolism in the liver occurs most intensively along the following metabolic pathways:

1) β - oxidation of IVFA;

2) decay of TAG, FL, cholesterol, mature HDL;

3) biosynthesis of transport forms of lipids (VLDL, HDL precursors);

4) biosynthesis of specific IVH, TAG, PL, cholesterol, cholesteryl esters, ketone bodies (acetyl-CoA →CH 3 COCH 2 COOH and

CH 3 -CHOH-CH 2 COOH).

The liver is involved in maintaining a constant level of fatty acids in the blood; if their number increases, the liver absorbs them and converts them into TAG, PL, ECS, VLDL. A decrease in the biosynthesis of phospholipids and a decrease in the formation of VLDL leads to an increase in the biosynthesis of TAG and their accumulation in hepatocytes, which is accompanied by fatty degeneration of the liver. Ketone bodies (acetoacetate, acetone, β-hydroxybutyrate) are synthesized only in liver hepatocytes from acetyl-CoA during the so-called β-hydroxy-β-methylglutaryl-CoA pathway. During fasting, with a reduced content of carbohydrates in food, and diabetes mellitus, the rate of synthesis of ketone bodies (ketogenesis) increases. From the liver, ketone bodies are transported by the bloodstream to peripheral tissues and organs (muscles, kidneys, brain, etc.), where they are converted into acetyl-CoA and provide energy in the citric acid cycle and CPE. The liver plays an important role in the metabolism of steroids, in particular cholesterol (C). The general pathway of cholesterol in the liver is:

1. cholesterol synthesized anew in the liver from acetyl-CoA (endogenous cholesterol);

2. CS, formed from cholesterol esters;

3. Cholesterol entering arterial blood as part of mature HDL;

4. CS formed from degraded forms of CM and VLDL.

In the liver, cholesterol (80%) is used for the formation of primary bile acids (cholic and chenodeoxycholic), for the construction of hepatocyte biomembranes, for the formation of VLDL and HDL precursors, and the synthesis of cholesterol esters.

In addition to numerous functions in intermediate metabolism, the liver plays an important role in digestion, since it produces bile.

Bile is a yellowish-brown liquid secretion, which consists of water (97%), free and conjugated bile acids and salts (1%), bilirubin and cholesterol, mineral salts, phospholipids, IVH.

There are hepatic bile and cystic bile, in which simple micelles are formed consisting of phospholipids, cholesterol and bile acids (2.5: 1: 12.5). Water-insoluble cholesterol is retained in bile in a dissolved state due to the presence of bile salts and phosphatidylcholine. When there is a lack of bile acids in the bile, cholesterol precipitates, promoting the formation of stones. If bile formation or outflow of bile is impaired, the digestion of lipids in the gastrointestinal tract is disrupted, which leads to steatorrhea.

The liver plays an important role in detoxifying foreign substances or xenobiotics. This is essential for preserving the life of the organism. Foreign substances enter the body with food, through the skin or with inhaled air and can be products of human economic activity, household chemicals, medications, ethanol. In the liver, toxic metabolites of the breakdown of nitrogen-containing substances are also inactivated: bilirubin, breakdown products of amino acids, biogenic amines, ammonia, hormones.

Hydrophilic xenobiotics are excreted in the urine. To remove hydrophobic substances, mechanisms have been developed in the process of evolution, representing two phases of detoxification: modification and conjugation. Possible modifications: hydroxylation (RH→ROH), sulfoxidation (R-S-R′→R-SO-R′), oxidative deamination (RNH 2 →R=O+NH 3), etc.

In the liver, microsomal oxidation (monooxygenase system), which is responsible for the neutralization of xenobiotics (foreign substances), is most active.

Hydroxylation is most often the result of chemical modification of toxic substances, occurring in the first phase of neutralization. In phase II, a conjugation reaction occurs; as a result of both phases, the resulting products are, as a rule, highly soluble and easily removed from the body.

The main enzymes involved in the oxidative system: cytochrome P 450 reductase - flavoprotein (coenzyme FADH 2 or FMNN 2), cytochrome P 450, which binds the lipophilic substance RH and an oxygen molecule in the active center. One O 2 atom attaches 2ē and goes into the O 2- form. The donor of electrons and protons is NADPH+H +, which is oxidized by cytochrome - P 450 - reductase, O 2- interacts with protons: O 2- + 2H + →H 2 O. The second atom of the oxygen molecule is included in the hydroxyl group of the substance RH to form R -OH, glycine can act as conjugants (during the neutralization of benzoic acid with the formation of hippuric acid); FAPS is a donor of a sulfuric acid residue; UDP is a glucuronide - a donor of a glucuronic acid residue. The last two conjugants are used in the neutralization of its own metabolites (indole, through indoxyl, is conjugated with FAPS, giving animal indican), as well as drugs (aspirin, after hydrolytic cleavage of acetate, is conjugated with UDP - glucuronide, forming a hydrophilic salicyl glucuronide, removed from the body in the urine).

Some xenobiotics (polycyclic aromatic hydrocarbons, aromatic amines, aflatoxins) undergo changes in the liver by enzymes of the monooxygenase system and turn into carcinogens. They can damage the DNA of genes, mutations in which contribute to the transformation of a normal cell into a tumor cell. The expression of such oncogenes leads to uncontrolled proliferation, i.e. to tumor development.

Thus, the epoxide formed as a result of the hydroxylation of benzanithracene covalently binds guanine, breaking the hydrogen bonds in the G≡C pair, thereby disrupting the interaction of DNA with proteins.

Nitrosamines formed from nitrous acid and secondary amines (HNO 2 +R 2 NH→R 2 N-N=O) convert cytosine into uracil, G≡C becomes GU. The complementary chain will already have SA, which, as a result of mutations, can turn into IA and its complementary pair will be AT, i.e. The coding meaning of DNA has completely changed.

The liver also plays an important role in the neutralization of bilirubin, which is formed in RES cells as a result of the breakdown of hemoglobin, myoglobin, catalase, cytochromes and other hemoproteins. The resulting bilirubin is insoluble in water, is transported in the blood in the form of a complex with albumin and is called “indirect” bilirubin. In the liver, 1/4 of the indirect bilirubin enters into a conjugation reaction with UDP-glucuronic acid, forming bilirubin diglucuronide, called “direct” bilirubin.

“Direct” bilirubin is excreted from the liver with bile into the small intestine, where glucuronic acid is cleaved under the influence of glucuronidase from intestinal microbes to form free bilirubin, which is further converted with the subsequent formation of bile pigments: stercobilinogen, stercobilin, urobilinogen, urobilin. An indicator of a violation of pigment metabolism in the liver is the content of “indirect”, “direct” and total bilirubin in the blood. An increase in the content of bilirubin in the blood leads to its deposition in tissues and causes jaundice of various etiologies. The main causes of hyperbilirubinemia are: increased hemolysis of red blood cells, deficiency and defect of the enzyme glucuronyltransferase, blockage of the bile ducts, imbalance between the formation and excretion of bilirubin, damage to hepatocytes (viruses, toxic hepatotropic substances), hepatitis, cirrhosis of the liver, etc.

Depending on the causes of hyperbilirubinemia, the following main types of jaundice are distinguished: hemolytic, parenchymal, obstructive, hereditary, neonatal jaundice, etc.

A diagnostic test to determine the origin of jaundice is the following normal values:

1) “direct” and “indirect” bilirubin in the blood;

2) bile pigments in urine and feces.

1) the blood contains total bilirubin from 8 to 20 µmol/l, with 25% (

5 µmol/l) of total bilirubin is “direct” bilirubin;

2) in urine - no bilirubin, urobilin - 1-4 mg/day;

3) up to 300 mg of stercobilin is released in feces per day (colors feces brown).

In hemolytic jaundice, hyperbilirubinemia occurs mainly due to increased hemolysis of red blood cells, resulting in an increase in:

1) the amount of indirect (free) bilirubin in the blood;

2) the amount of urobilin in the urine (dark urine);

3) the amount of stercobilin in the stool (dark stool).

The skin and mucous membranes are yellow. With parenchymal (hepatocellular) jaundice, liver cells are damaged, as a result of which their permeability increases. Therefore, with parenchymal jaundice:

1) the amount of both “indirect” and “direct” bilirubin in the blood increases (bile enters directly into the blood);

2) the amount of urobilin in the urine decreases and “direct” bilirubin is detected;

3) the content of stercobilin in feces decreases.

With obstructive (mechanical) jaundice, the outflow of bile is impaired (blockage of the common bile duct), which leads to:

1) in the blood - to an increase in “direct” bilirubin;

2) in urine - to an increase in “direct” bilirubin and the absence of urobilin;

3) in feces - to the absence of bile pigments, feces are discolored.

There are several known diseases in which jaundice is caused by hereditary disorders of bilirubin metabolism. Approximately 5% of the population is diagnosed with jaundice caused by genetic disorders in the structure of proteins and enzymes responsible for the uptake of indirect bilirubin into the liver (Gilbert syndrome), for its conjugation with glucuronic acid, caused by a violation of the glucuronidation reaction in the liver (Cragler-Najjar syndrome I and II types), a violation of the active transport of bilirubin glucuronides formed in the liver into bile (Dabin-Rotor-Johnson syndrome).

Differential diagnosis of hereditary jaundice

Syndrome	Defect	Clinical manifestations
Unconjugated hyperbilirinemia
Crigler-Nayjar type I* (congenital non-hemolytic jaundice)	Lack of activity, bilirubin - UDP-glucuronyltransferase (cannot be treated with phenobarbital - an inducer of the UDP-glucuronyltransferase gene)	In blood o.b., n.b., k.b.↓, in urine u↓, k.b.↓, in feces c↓.
Crigler-Nayyar-II type	The synthesis of UDP glucuronyltransferase, which catalyzes the addition of the second glucuronyl group, is impaired (can be treated with phenobarbital and phototherapy)
Gilbert	Hepatocytes do not absorb bilirubin, conjugation is reduced	In the blood b.b., n.b., c.b.N↓, in the urine c.b.↓, u.↓, in feces c↓.
Conjugated hyperbilirubinemia
Dabin-Rotor-Johnson	Conjugated bilirubin does not enter bile	In blood ob.b., n.b., c.b., in urine c.b.↓, y↓, in feces c↓.

about. – total bilirubin,

n.b. – unconjugated bilirubin,

k.b. -. conjugated bilirubin,

c – stercobilin,

y – urobilin.

* - children die at an early age due to the development of bilirubin encephalopathy.

Familial hyperbilirubinemia of newborns is associated with the presence of competitive inhibitors of bilirubin conjugation (estrogen, free fatty acids) in breast milk. During breastfeeding, these inhibitors lead to hyperbilirubinemia (transient hyperbilirubinemia), which disappears when switching to artificial feeding.

LABORATORY LESSON ON LIVER BIOCHEMISTRY

Purpose of the lesson:

1. Know the main functions of the liver, the features of the ways of neutralizing xenobiotics and metabolites in the liver, the formation and neutralization of bilirubin.

2. Be able to quantify the concentration of direct and indirect bilirubin in blood serum and bile pigments in urine to diagnose the main types of jaundice.

3. Familiarize yourself with the types of hereditary jaundice.

Principle of the method. Bilirubin gives a pink color with Ehrlich's diazoreagent. The intensity of the staining is used to judge the concentration of bilirubin. Direct bilirubin (synonyms: bilirubin-glucuronide, conjugated bilirubin, conjugated bilirubin) is determined by the Ehrlich color reaction in the absence of organic solvents. Total (direct, indirect) bilirubin is determined in the presence of alcohol, which ensures the interaction of all forms of bilirubin with Ehrlich's diazoreagent. Indirect bilirubin (synonyms: free bilirubin, unconjugated bilirubin) is determined by the difference between total and direct.

COURSE WORK:

ANALYSIS OF BIOCHEMICAL INDICATORS OF LIVER FUNCTION IN NORMAL AND PATHOLOGY

Contents

Introduction

1.1.2 Regulation of lipid metabolism

1.1.3 Regulation of protein metabolism

1.2 Urea-forming function

1.3 Bile formation and excretory function

1.4 Biotransformation (neutralizing) function

2. Liver diseases and laboratory diagnosis of liver diseases

2.1 Basics of clinical laboratory diagnosis of liver diseases

2.2 Main clinical and laboratory syndromes for liver damage

2.2.1 Cytolysis syndrome

2.2.4 Inflammation syndrome

2.2.5 Liver shunt syndrome

Conclusion

The biochemistry of the liver includes both the occurrence of normal metabolic processes and metabolic disorders with the development of pathology. Studying all aspects of liver biochemistry will allow you to see a picture of a normally functioning organ and its participation in the functioning of the entire body and maintaining homeostasis. Also, during normal liver function, the integration of all major metabolisms in the body occurs, and it is possible to observe the initial stages of metabolism (for example, during the primary absorption of substances from the intestine) and the final stages with the subsequent removal of metabolic products from the body.

When liver function is impaired, metabolism shifts in a certain direction, so it is necessary to study the pathological conditions of the organ for further diagnosis of diseases. Currently, this is especially important, since liver diseases are progressing, and sufficiently good treatment methods do not yet exist. Such diseases primarily include viral hepatitis, liver cirrhosis (often with systematic alcohol consumption and other harmful external influences associated with unfavorable ecology), metabolic changes due to poor nutrition, and liver cancer. Therefore, early diagnosis of these diseases, which can be based on biochemical indicators, is very important.

The purpose of the course work is to examine the functions of the liver and compare the biochemical indicators of the functioning of this organ in normal and pathological conditions; also an indication of the basic principles of laboratory diagnostics, a brief description of hepatitis syndromes of various etiologies and examples.

1. Functional biochemistry of the liver

Conventionally, liver functions according to biochemical indicators can be divided into: regulatory-homeostatic function, including the main types of metabolism (carbohydrate, lipid, protein, vitamin metabolism, water-mineral and pigment metabolism), urea-forming, bile-forming and neutralizing functions. Such basic functions and their regulation are discussed in detail later in this chapter.

1.1 Regulatory and homeostatic function of the liver

The liver is the central organ of chemical homeostasis, where all metabolic processes occur extremely intensively and where they are closely intertwined.

1.1.1 Carbohydrate metabolism in the liver and its regulation

Monosaccharides (in particular glucose) enter the liver through the portal vein and undergo various transformations. For example, when there is an excess intake of glucose from the intestine, it is deposited in the form of glycogen; glucose is also produced by the liver during glycogenolysis and gluconeogenesis, enters the blood and is consumed by most tissues. Regulation of carbohydrate metabolism is carried out due to the fact that the liver is practically the only organ that maintains a constant level of glucose in the blood even under fasting conditions.

The fate of monosaccharides varies depending on their nature, their content in the general bloodstream, and the needs of the body. Some of them will go to the hepatic vein to maintain homeostasis, primarily of blood glucose, and meet the needs of the organs. The concentration of glucose in the blood is determined by the balance of the rates of its entry, on the one hand, and consumption by tissues, on the other. In a post-absorptive state (a post-absorptive state develops 1.5-2 hours after a meal, also called true or metabolic saturation. A typical post-absorptive state is considered to be the state in the morning before breakfast, after about a ten-hour night break in eating) and normal glucose concentration in blood is 60-100 mg/dl (3.3-5.5 mol). And the liver uses the rest of the monosaccharides (mainly glucose) for its own needs.

Glucose metabolism occurs intensively in hepatocytes. Glucose received from food is converted only in the liver with the help of specific enzyme systems into glucose-6-phosphate (only in this form is glucose used by cells). Phosphorylation of free monosaccharides is an obligatory reaction in the pathway of their use; it leads to the formation of more reactive compounds and therefore can be considered an activation reaction. Galactose and fructose coming from the intestinal tract, with the participation of galactokinase and fructokinase, respectively, are phosphorylated at the first carbon atom:

Glucose entering liver cells is also phosphorylated using ATP. This reaction is catalyzed by the enzymes hexokinase and glucokinase.

liver pathology diagnosis disease

Hexokinase has a high affinity for glucose (K m

Along with other mechanisms, this prevents excessive increases in peripheral blood glucose concentrations during digestion.

The formation of glucose-6-phosphate in the cell is a kind of “trap” for glucose, since the cell membrane is impermeable to phosphorylated glucose (there are no corresponding transport proteins). In addition, phosphorylation reduces the concentration of free glucose in the cytoplasm. As a result, favorable conditions are created for facilitated diffusion of glucose into liver cells from the blood.

The reverse reaction of converting glucose-6-phosphate into glucose is also possible under the action of glucose-6-phosphatase, which catalyzes the removal of the phosphate group hydrolytically.

The resulting free glucose is able to diffuse from the liver into the blood. In other organs and tissues (except for the kidneys and intestinal epithelial cells), there is no glucose-6-phosphatase, and therefore only phosphorylation takes place there, without a reverse reaction, and the release of glucose from these cells is impossible.

Glucose-6-phosphate can be converted to glucose-1-phosphate with the participation of phosphoglucomutase, which catalyzes the reversible reaction.

Glucose-6-phosphate can also be used in various transformations, the main of which are: glycogen synthesis, catabolism with the formation of CO 2 and H 2 O or lactate, pentose synthesis. At the same time, during the metabolism of glucose-6-phosphate, intermediate products are formed that are subsequently used for the synthesis of amino acids, nucleotides, glycerol and fatty acids. Thus, glucose-6-phosphate is not only a substrate for oxidation, but also a building material for the synthesis of new compounds (Appendix 1).

So, let's look at the oxidation of glucose and glucose-6-phosphate in the liver. This process goes in two ways: dichotomous and apotomic. The dichotomous pathway is glycolysis, which includes “anaerobic glycolysis”, ending with the formation of lactic acid (lactate) or ethanol and CO 2 and “aerobic glycolysis” - the breakdown of glucose, passing through the formation of glucose-6-phosphate, fructose bisphosphate and pyruvate, both in the absence and in the presence of oxygen (aerobic metabolism of pyruvate goes beyond carbohydrate metabolism, but can be considered as its final stage: oxidation of the product of glycolysis - pyruvate).

The apotomic pathway of glucose oxidation or the pentose cycle consists of the formation of pentoses and the return of pentoses to hexoses, as a result of which one glucose molecule breaks down and CO 2 is formed.

Glycolysis under anaerobic conditions- a complex enzymatic process of glucose breakdown that occurs without oxygen consumption. The end product of glycolysis is lactic acid. During glycolysis, ATP is produced.

The process of glycolysis occurs in the hyaloplasm (cytosol) of the cell and is conventionally divided into eleven stages, which are respectively catalyzed by eleven enzymes:

1. Phosphorylation of glucose and the formation of glucose-6-phosphate is the transfer of an orthophosphate residue to glucose using the energy of ATP. The catalyst is hexokinase. This process has been discussed above.

1. Conversion of glucose-6-phosphate by the enzyme glucose-6-phosphate isomerase into fructose 6-phosphate:
2. Fructose-6-phosphate is phosphorylated again due to the second ATP molecule, the reaction is catalyzed by phosphofructokinase:

The reaction is irreversible, occurs in the presence of magnesium ions and is the slowest reaction of glycolysis.

1. Under the influence of the enzyme aldolase, fructose-1,6-bisphosphate is split into two phosphotrioses:

1. Isomerization reaction of triose phosphates. Catalyzed by the enzyme triosephosphate isomerase:

1. Glyceraldehyde-3-phosphate, in the presence of the enzyme glyceraldehyde phosphate dehydrogenase, the coenzyme NAD and inorganic phosphate, undergoes a kind of oxidation with the formation of 1,3-bisphosphoglyceric acid and the reduced form of NAD - NAD*H 2:

1. The reaction is catalyzed by phosphoglycerate kinase, transferring the phosphate group at position 1 to ADP to form ATP and 3-phosphoglyceric acid (3-phosphoglycerate):

1. Intramolecular transfer of the remaining phosphate group, and 3-phosphoglyceric acid is converted to 2-phosphorylceric acid (2-phosphoglycerate):

The reaction is easily reversible and occurs in the presence of magnesium ions.

9. The reaction is catalyzed by the enzyme enolase, 2-phosphoglyceric acid, as a result of the elimination of a water molecule, becomes phosphoenolpyruvic acid (phosphoenolpyruvate), and the phosphate bond in position 2 becomes high-energy:

1. Breaking the high-energy bond and transferring the phosphate residue from phosphoenolpyruvate to ADP. Crystallized by the enzyme pyruvate kinase:

11. Reduction of pyruvic acid and formation of lactic acid (lactate). The reaction occurs with the participation of the enzyme lactate dehydrogenase and the coenzyme NAD*H 2, formed in the sixth reaction:

Glycolysis under aerobic conditions. There are three parts to this process:

1. transformations specific to glucose, culminating in the formation of pyruvate (aerobic glycolysis);

2. general path of catabolism (oxidative decarboxylation of pyruvate and citrate cycle);

3. mitochondrial electron transport chain.

As a result of these processes, glucose in the liver breaks down to C0 2 and H 2 0, and the released energy is used for the synthesis of ATP (Appendix 2).

The metabolism of carbohydrates in the liver includes only glucose-specific transformations, where the breakdown of glucose to pyruvate occurs, which can be divided into two stages:

1. From glucose to glyceraldehyde phosphate. In the reactions, phosphate residues are incorporated into hexoses and the hexose is converted into triose (Appendix 3). The reactions of this stage are catalyzed by the following enzymes: hexokinase or glucokinase (1); phosphoglucoisomerase (2); phosphofructokinase (3); Fructose 1,6-bisphosphate aldolase (4) ; phosphotriose isomerase (5)

2. From glyceraldehyde phosphate to pyruvate. These are reactions associated with the synthesis of ATP. The stage ends with the conversion of each glucose molecule into two molecules of glyceraldehyde phosphate (Appendix 4). Five enzymes are involved in the reactions: glyceraldehyde phosphate dehydrogenase (6); phosphoglycerate kinase (7); phosphoglyceromutase (8); enolase (9); pyruvate kinase (10).

Pentose phosphate (phosphogluconate) pathway Glucose conversion provides the cell with hydrogenated NADP for reductive syntheses and pentoses for nucleotide synthesis. The pentose phosphate pathway can be divided into two parts - the oxidative and non-oxidative pathways.

1. The oxidative pathway includes two dehydrogenation reactions, where NADP serves as a hydrogen acceptor (Appendix 5). In the second reaction, decarboxylation occurs simultaneously, the carbon chain is shortened by one carbon atom, and pentoses are obtained.
2. The non-oxidative pathway is much more complicated. There are no dehydrogenation reactions here; it can only serve for the complete decomposition of pentoses (to C0 2 and H 2 0) or for the conversion of pentoses into glucose (Appendix 6). The starting materials are five molecules of fructose-6-phosphate, containing a total of 30 carbon atoms, the final product of the reaction is six molecules of ribose-5-phosphate, also containing a total of 30 carbon atoms.

The oxidative pathway for the formation of pentoses and the pathway for the return of pentoses to hexoses together constitute a cyclic process:

In this cycle, one glucose molecule completely disintegrates in one revolution, all six carbon atoms of which are converted into CO 2.

Also in the liver there is a process opposite to glycolysis - gluconeogenesis. Gluconeogenesis- the process of synthesis of glucose from non-carbohydrate substances. Its main function is to maintain blood glucose levels during periods of prolonged fasting and intense physical activity. Gluconeogenesis provides the synthesis of 80-100 g of glucose per day. The primary substrates of gluconeogenesis are lactate, amino acids and glycerol. The inclusion of these substrates in gluconeogenesis depends on the physiological state of the organism. Lactate is a product of anaerobic glycolysis. It is formed under any conditions of the body in red blood cells and working muscles. Thus, lactate is constantly used in gluconeogenesis. Glycerol is released during the hydrolysis of fats in adipose tissue during fasting or prolonged physical activity. Amino acids are formed as a result of the breakdown of muscle proteins and are included in gluconeogenesis during prolonged fasting or prolonged muscle work. It should be noted that glycolysis occurs in the cytosol, and some of the gluconeogenesis reactions occur in mitochondria.

Gluconeogenesis basically follows the same pathway as glycolysis, but in the opposite direction (Appendix 7). However, the three reactions of glycolysis are irreversible, and at these stages the reactions of gluconeogenesis differ from those of glycolysis.

The conversion of pyruvate to phosphoenolpyruvate (irreversible stage I) is carried out with the participation of two enzymes: pyruvate carboxylase and phosphoenolpyruvate carboxykinase:

The other two irreversible steps are catalyzed by fructose-1,6-bisphosphate phosphatase and glucose-6-phosphate phosphatase:

Each of the irreversible reactions of glycolysis, together with the corresponding reaction of gluconeogenesis, forms a substrate cycle (Appendix 7, reactions 1, 2, 3).

Glucose synthesis (gluconeogenesis from amino acids and glycerol). Glucose in the liver can be synthesized from amino acids and glycerol. During the catabolism of amino acids, pyruvate or oxaloacetate are formed as intermediate products, which can be included in the gluconeogenesis pathway at the stage of the first substrate cycle (Appendix 7, reaction 1). Glycerol is formed during the hydrolysis of fats and can be converted into glucose (Appendix 8). Amino acids and glycerol are used for glucose synthesis mainly during fasting or when the diet is low in carbohydrates (carbohydrate starvation).

Gluconeogenesis can also occur from lactate. Lactic acid is not the end product of metabolism, but its formation is a dead-end metabolic pathway: the only way to use lactic acid is associated with its conversion back into pyruvate with the participation of the same lactate dehydrogenase:

From the cells in which glycolysis occurs, the resulting lactic acid enters the blood and is captured mainly by the liver, where it is converted into pyruvate. Pyruvate in the liver is partially oxidized and partially converted into glucose - the Cori cycle, or glucosolactate cycle:

In the body of an adult, about 80 g of glucose can be synthesized per day, mainly in the liver. The biological significance of gluconeogenesis lies not only in the return of lactate to the metabolic pool of carbohydrates, but also in the provision of glucose to the brain when there is a lack of carbohydrates in the body, for example, during carbohydrate or complete starvation.

Glycogen synthesis (glycogenesis). As mentioned above, part of the glucose that enters the liver is used in the synthesis of glycogen. Glycogen is a branched homopolymer of glucose in which glucose residues are connected in linear regions by an a-1,4-glycosidic bond. At branch points, the monomers are connected by a-1,6-glycosidic bonds. These bonds are formed with approximately every tenth glucose residue. This results in a tree-like structure with a molecular weight of >10 7 D, which corresponds to approximately 50,000 glucose residues (Appendix 9). When glucose polymerizes, the solubility of the resulting glycogen molecule decreases and, consequently, its effect on the osmotic pressure in the cell. This circumstance explains why glycogen is deposited in the cell, and not free glucose.

Glycogen is stored in the cytosol of the cell in the form of granules with a diameter of 10-40 nm. After eating a meal rich in carbohydrates, the glycogen reserve in the liver can be approximately 5% of its mass.

The breakdown of liver glycogen serves mainly to maintain blood glucose levels in the post-absorptive period. Therefore, the glycogen content in the liver changes depending on the rhythm of nutrition. With prolonged fasting, it decreases to almost zero.

Glycogen is synthesized during digestion (1-2 hours after eating carbohydrate foods). The synthesis of glycogen from glucose requires energy.

First of all, glucose undergoes phosphorylation with the participation of the enzymes hexokinase and glucokinase. Next, glucose-6-phosphate, under the influence of the enzyme phosphoglucomutase, is converted into glucose-1-phosphate.

The resulting glucose-1-phosphate is already directly involved in glycogen synthesis.

At the first stage of synthesis, glucose-1-phosphate interacts with UTP (uridine triphosphate), forming uridine diphosphate glucose (UDP-glucose) and pyrophosphate. This reaction is catalyzed by the enzyme glucose-1-phosphate uridylyltransferase (UDPG-pyrophosphorylase) (Appendix 10).

At the second stage - the stage of glycogen formation - the transfer of the glucose residue included in UDP-glucose to the glucoside chain of glycogen (“seed” amount) occurs (Appendix 11). In this case, a b-1,4-glycosidic bond is formed between the first carbon atom of the added glucose residue and the 4-hydroxyl group of the glucose residue of the chain. This reaction is catalyzed by the enzyme glycogen synthase. The resulting UDP is then phosphorylated back into UTP at the expense of ATP, and thus the entire cycle of glucose-1-phosphate conversion begins all over again.

It has been established that glycogen synthase is unable to catalyze the formation of the b-1,6-glycosidic bond present at the branch points of glycogen. This process is catalyzed by a special enzyme called glycogen branching enzyme, or amylo-1,4-1,6-transglucosidase. The latter catalyzes the transfer of a terminal oligosaccharide fragment consisting of 6 or 7 glucose residues from the non-reducing end of one of the side chains, containing at least 11 residues, to the 6-hydroxyl group of a glucose residue of the same or another glycogen chain. As a result, a new side chain is formed. Branching increases the rate of glycogen synthesis and breakdown.

Glycogen breakdown or him mobilization occur in response to an increase in the body's need for glucose. Liver glycogen breaks down mainly in the intervals between meals, the breakdown accelerates during physical work. The breakdown of glycogen occurs with the participation of two enzymes: glycogen phosphorylase and an enzyme with dual specificity - 4: 4-transferase-b-1,6-glycosidase. Glycogen phosphorylase catalyzes the phosphorolysis of the 1,4-glycosidic bond of the non-reducing ends of glycogen, the glucose residues are cleaved off one by one in the form of glucose-1-phosphate (Appendix 12). In this case, glycogen phosphorylase cannot cleave glucose residues from short branches containing less than five glucose residues; such branches are removed by 4:4-transferase-b-1,6-glycosidase. This enzyme catalyzes the transfer of a three-residue fragment of a short branch to a terminal glucose residue of a longer branch; in addition, it hydrolyzes the 1,6-glycosidic bond and thus removes the last residue of the branch (Appendix 13).

Fasting for 24 hours leads to the almost complete disappearance of glycogen in liver cells. However, with rhythmic nutrition, each glycogen molecule can exist indefinitely: in the absence of digestion and the entry of glucose into tissues, glycogen molecules decrease due to the splitting of peripheral branches, and after the next meal they grow again to their previous sizes.

Glucose-1-phosphate, formed from glycogen, with the participation of phosphoglucomutase is converted into glucose-6-phosphate, the further fate of which in the liver and muscles is different. In the liver, glucose-6-phosphate is converted into glucose with the participation of glucose-6-phosphatase, glucose enters the blood and is used in other organs and tissues.

Regulation of glycogenesis and glycogenolysis processes carried out by hormones: insulin, glucagon, adrenaline. The primary signal for the synthesis of insulin and glucagon is a change in the concentration of glucose in the blood. Insulin and glucagon are constantly present in the blood, but when the absorptive period changes to the postabsorptive period, their relative concentration changes, which is the main factor that switches glycogen metabolism in the liver. The ratio of the concentration of insulin in the blood to the concentration of glucagon is called the “insulin-glucagon index.” In the post-absorptive period, the insulin-glucagon index decreases, and glucagon concentration becomes decisive in the regulation of glucose and blood concentrations. During digestion, the influence of insulin predominates, since the insulin-glucagon index in this case increases. In general, insulin has the opposite effect on glycogen metabolism than glucagon. Insulin lowers the concentration of glucose in the blood during digestion.

The hormone adrenaline stimulates the release of glucose from the liver into the blood in order to provide tissues (mainly the brain and muscles) with “fuel” in an extreme situation.

A regulatory factor in glycogen metabolism is also the value K m glucokinase, which is much higher than the K m of hexokinase - the liver should not consume glucose for the synthesis of glycogen if its amount in the blood is within normal limits.

Lipid metabolism in the liver includes the biosynthesis of various lipids (cholesterol, triacylglycerol, phosphoglycerides, sphingomyelin, etc.) that enter the blood and are distributed to other tissues and the combustion (oxidation) of fatty acids with the formation of ketone bodies, which are used as an energy source for extrahepatic tissues.

The delivery of fatty acids to the site of oxidation - to the mitochondria of liver cells - occurs in a complex way: with the participation of albumin, fatty acids are transported into the cell; with the participation of special proteins - transport within the cytosol; with the participation of carnitine - transport of fatty acids from the cytosol to the mitochondria.

Fatty acid oxidation process consists of the following main stages.

1. Activation of fatty acids. Activation occurs on the outer surface of the mitochondrial membrane with the participation of ATP, coenzyme A (HS-KoA) and Mg 2+ ions. The reaction is catalyzed by the enzyme acyl-CoA synthetase:

Activation occurs in 2 stages. First, the fatty acid reacts with ATP to form acyladenylate, then the sulfhydryl group of CoA acts on the acyladenylate tightly bound to the enzyme to form acyl-CoA and AMP.

This is followed by the transport of fatty acids into the mitochondria. Carnitine serves as a carrier of activated long-chain fatty acids across the inner mitochondrial membrane. The acyl group is transferred from the sulfur atom of CoA to the hydroxyl group of carnitine.

2. Acylcarnitine is formed, which diffuses through the inner mitochondrial membrane:

The reaction occurs with the participation of a specific cytoplasmic enzyme, carnitine acyltransferase. After acylcarnitine passes through the mitochondrial membrane, a reverse reaction occurs - the cleavage of acylcarnitine with the participation of HS-CoA and mitochondrial carnitine acyltransferase:

3. Intramitochondrial oxidation of fatty acids. The process of fatty acid oxidation in cell mitochondria includes several sequential reactions.

First stage of dehydrogenation. Acyl-CoA in mitochondria undergoes enzymatic dehydrogenation, while acyl-CoA loses 2 hydrogen atoms in the b- and c-positions, turning into the CoA ester of an unsaturated acid. The reaction is catalyzed by acyl-CoA dehydrogenase, the product is enoyl-CoA:

Hydration stage. Unsaturated acyl-CoA (enoyl-CoA), with the participation of the enzyme enoyl-CoA hydratase, attaches a water molecule. As a result, β-hydroxyacyl-CoA (or 3-hydroxyacyl-CoA) is formed:

Second stage of dehydrogenation. The resulting β-hydroxyacyl-CoA (3-hydroxyacyl-CoA) is then dehydrogenated. This reaction is catalyzed by NAD-dependent dehydrogenases:

Thiolase reaction. Cleavage of 3-oxoacyl-CoA by the thiol group of the second CoA molecule. As a result, an acyl-CoA shortened by two carbon atoms and a two-carbon fragment in the form of acetyl-CoA are formed. This reaction is catalyzed by acetyl-CoA acyltransferase (β-ketothiolase):

The resulting acetyl-CoA undergoes oxidation in the tricarboxylic acid cycle, and acyl-CoA, shortened by two carbon atoms, again repeatedly goes through the entire path of β-oxidation until the formation of butyryl-CoA (4-carbon compound), which in turn is oxidized to 2 acetyl-CoA molecules.

Biosynthesis of fatty acids. The synthesis of fatty acids occurs in the cytoplasm of the cell. Mitochondria mainly involve elongation of existing fatty acid chains. It has been established that palmitic acid (16 carbon atoms) is synthesized in the cytoplasm of liver cells, and in the mitochondria of these cells from this palmitic acid or from fatty acids of exogenous origin, i.e. coming from the intestines, fatty acids containing 18, 20 and 22 carbon atoms are formed.

The mitochondrial system of fatty acid biosynthesis includes a slightly modified sequence of β-oxidation reactions, and only carries out the elongation of medium-chain fatty acids existing in the body, while the complete biosynthesis of palmitic acid from acetyl-CoA actively occurs in the cytosol, i.e. outside the mitochondria, along a completely different path.

The extramitochondrial fatty acid biosynthesis system (lipogenesis) is located in the soluble (cytosolic) fraction of liver cells. The biosynthesis of fatty acids occurs with the participation of NADPH, ATP, Mn2+ and HCO3- (as a source of CO2); the substrate is acetyl-CoA, the final product is palmitic acid.

Educationunsaturated fatty acids. Elongation of fatty acids.

The two most common monounsaturated fatty acids, palmitoleic and oleic, are synthesized from palmitic and stearic acids. These transformations occur in the microsomes of liver cells. Only activated forms of palmitic and stearic acids undergo transformation. The enzymes involved in these transformations are called desaturases. Along with the desaturation of fatty acids (formation of double bonds), their lengthening (elongation) also occurs in microsomes, and both of these processes can be combined and repeated. Elongation of the fatty acid chain occurs by sequential addition of two-carbon fragments to the corresponding acyl-CoA with the participation of malonyl-CoA and NADPH. The enzyme system that catalyzes the elongation of fatty acids is called elongase. The pathways for the conversion of palmitic acid in desaturation and elongation reactions are presented in Appendix 14.

Triglyceride biosynthesis. Triglyceride synthesis occurs from glycerol and fatty acids (mainly stearic, palmitic and oleic). The first pathway of triglyceride biosynthesis in the liver proceeds through the formation of b-glycerophosphate (glycerol-3-phosphate) as an intermediate compound; glycerol is phosphorylated by ATP to form glycerol-3-phosphate:

The second pathway is mainly associated with the processes of glycolysis and glycogenolysis. It is known that in the process of glycolytic breakdown of glucose, dihydroxyacetone phosphate is formed, which, in the presence of cytoplasmic glycerol-3-phosphate dehydrogenase, can be converted into glycerol-3-phosphate:

The glycerol-3-phosphate formed in one way or another is sequentially acylated by two molecules of the CoA derivative of the fatty acid. As a result, phosphatidic acid (phosphatidate) is formed:

Acylation of glycerol-3-phosphate occurs sequentially, i.e. in 2 stages. First, glycerol 3-phosphate acyltransferase catalyzes the formation of lysophosphatidate. Next, phosphatidic acid is hydrolyzed by phosphatidate phosphohydrolase to 1,2-diglyceride (1,2-diacylglycerol):

The 1,2-diglyceride is then acylated by a third acyl-CoA molecule and converted to a triglyceride (triacylglycerol). This reaction is catalyzed by diacylglycerol acyltransferase:

It has been established that most of the enzymes involved in the biosynthesis of triglycerides are located in the endoplasmic reticulum, and only a few, for example glycerol-3-phosphate acyltransferase, are in mitochondria.

Phospholipid metabolism. Phospholipids play an important role in the structure and function of cell membranes, activation of membrane and lysosomal enzymes, in the conduction of nerve impulses, blood clotting, immunological reactions, processes of cell proliferation and tissue regeneration, in the transfer of electrons in the chain of respiratory enzymes. A special role is played by phospholipids in the formation of lipoprotein complexes. The most important phospholipids are synthesized mainly in the endoplasmic reticulum of the cell.

A central role in the biosynthesis of phospholipids is played by 1,2-diglycerides (in the synthesis of phosphatidylcholines and phosphatidylethanolamines), phosphatidic acid (in the synthesis of phosphatidylinositols) and sphingosine (in the synthesis of sphingomyelins). Cytidine triphosphate (CTP) is involved in the synthesis of almost all phospholipids.

Cholesterol biosynthesis. In the synthesis of cholesterol, three main stages can be distinguished: I - conversion of active acetate into mevalonic acid, II - formation of squalene from mevalonic acid, III - cyclization of squalene into cholesterol.

Let's consider the stage of conversion of active acetate to mevalonic acid. The initial step in the synthesis of mevalonic acid from acetyl-CoA is the formation of acetoacetyl-CoA through a reversible thiolase reaction. Then, with the subsequent condensation of acetoacetyl-CoA with the 3rd molecule of acetyl-CoA with the participation of hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), β-hydroxy-β-methylglutaryl-CoA is formed. Next, β-hydroxy-β-methylglutaryl-CoA, under the action of the regulatory enzyme NADP-dependent hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), as a result of the reduction of one of the carboxyl groups and the cleavage of HS-KoA, is converted into mevalonic acid.

Along with the classical pathway of mevalonic acid biosynthesis, there is a second pathway in which β-hydroxy-β-methylglutaryl-S-ACP is formed as an intermediate substrate. The reactions of this pathway are identical to the initial stages of fatty acid biosynthesis up to the formation of acetoacetyl-S-ACP. Acetyl-CoA carboxylase, an enzyme that converts acetyl-CoA into malonyl-CoA, takes part in the formation of mevalonic acid along this pathway.

At stage II of cholesterol synthesis, mevalonic acid is converted to squalene. Stage II reactions begin with the phosphorylation of mevalonic acid with the help of ATP. As a result, a 5-phosphoric ester is formed, and then a 5-pyrophosphoric ester of mevalonic acid. 5-pyrophosphomevalonic acid, as a result of subsequent phosphorylation of the tertiary hydroxyl group, forms an unstable intermediate product - 3-phospho-5-pyrophosphomevalonic acid, which, decarboxylated and losing the phosphoric acid residue, converted to isopentenyl pyrophosphate. The latter isomerizes to dimethylallyl pyrophosphate. Both isomeric isopentenyl pyrophosphates (dimethylallyl pyrophosphate and isopentenyl pyrophosphate) are then condensed to release pyrophosphate and form geranyl pyrophosphate. Isopentenyl pyrophosphate is again added to geranyl pyrophosphate. This reaction produces farnesyl pyrophosphate. In the final reaction of this stage, squalene is formed as a result of NADPH-dependent reductive condensation of 2 molecules of farnesyl pyrophosphate.

At stage III of cholesterol biosynthesis, squalene, under the influence of squalene oxidocyclase, cyclizes to form lanosterol. The subsequent conversion of lanosterol to cholesterol involves a series of reactions involving the removal of three methyl groups, saturation of the double bond in the side chain, and displacement of the double bond.

The general scheme of cholesterol synthesis is presented in Appendix 15.

Metabolism of ketone bodies. The term ketone (acetone) bodies means acetoacetic acid (acetoacetate) CH3COCH2COOH, β-hydroxybutyric acid (β-hydroxybutyrate, or D-3-hydroxybutyrate) CH3CHONCH2COOH and acetone CH3COCH3.

The formation of ketone bodies occurs in several stages (Appendix 16). At the first stage, acetoacetyl-CoA is formed from 2 molecules of acetyl-CoA. The reaction is catalyzed by the enzyme acetyl-CoA acetyltransferase (3-ketothiolase). Acetoacetyl-CoA then interacts with another acetyl-CoA molecule. The reaction occurs under the influence of the enzyme hydroxymethylglutaryl-CoA synthetase. The resulting β-hydroxy-β-methylglutaryl-CoA is capable of being cleaved into acetoacetate and acetyl-CoA by the action of hydroxymethylglutaryl-CoA lyase. Acetoacetate is reduced with the participation of NAD-dependent D-3-hydroxybutyrate dehydrogenase, resulting in the formation of D-β-hydroxybutyric acid (D-3-hydroxybutyrate).

There is a second route for the synthesis of ketone bodies. Formed by the condensation of 2 molecules of acetyl-CoA, acetoacetyl-CoA is capable of splitting off coenzyme A and converting into acetoacetate. This process is catalyzed by the enzyme acetoacetyl-CoA hydrolase (deacylase). However, the second pathway for the formation of acetoacetic acid (acetoacetate) is not significant, since deacylase activity in the liver is low.

In the blood of a healthy person, ketone bodies are contained only in very small concentrations (0.03-0.2 mmol/l in blood serum). The important role of ketone bodies in maintaining energy balance should be emphasized. Ketone bodies provide fuel to muscles, kidneys, and act possibly as part of a feedback regulatory mechanism to prevent excessive mobilization of fatty acids from fat stores. The liver is an exception in this sense; it does not use ketone bodies as energy material. From liver mitochondria, these compounds diffuse into the blood and are transported to peripheral tissues.

The liver is the central site of IVF exchange. They come here from the intestines, fat depots as part of blood plasma albumin.

Regulation of the synthesis and breakdown of fats in the liver. Liver cells have active enzyme systems for both synthesis and breakdown of fats. The regulation of fat metabolism is largely determined by the regulation of fatty acid metabolism, but is not limited to these mechanisms. The synthesis of fatty acids and fats is activated during digestion, and their breakdown is activated in the post-absorptive state and during fasting. In addition, the rate of fat utilization is proportional to the intensity of muscle work. The regulation of fat metabolism is closely related to the regulation of glucose metabolism. As in the case of glucose metabolism, the hormones insulin, glucagon, adrenaline and the processes of switching phosphorylation-dephosphorylation of proteins play an important role in the regulation of fat metabolism.

Regulation of protein metabolism in the liver is carried out due to the intensive biosynthesis of proteins and the oxidation of amino acids. During the day, the human body produces about 80-100 g of protein, half of which is in the liver. During fasting, the liver is the fastest to use up its reserve proteins to supply other tissues with amino acids. Protein loss in the liver is approximately 20%; while in other organs it is no more than 4%. The proteins of the liver itself are normally completely renewed every 20 days. The liver sends most of the synthesized proteins into the blood plasma. When necessary (for example, during complete or protein fasting), these proteins also serve as sources of essential amino acids.

Having entered the liver through the portal vein, amino acids undergo a number of transformations, and a significant part of the amino acids is carried by the blood throughout the body and is used for physiological purposes. The liver ensures the balance of free amino acids in the body by synthesizing non-essential amino acids and redistributing nitrogen. Absorbed amino acids are primarily used as building materials for the synthesis of specific tissue proteins, enzymes, hormones and other biologically active compounds. A certain amount of amino acids undergoes breakdown with the formation of the final products of protein metabolism (CO2, H2O and NH3) and the release of energy.

All albumins, 75-90% of β-globulins (β 1 -antitrypsin, β 2 -macroglobulin - protease inhibitors, proteins of the acute phase of inflammation), 50% of plasma β-globulins are synthesized by hepatocytes. The liver synthesizes protein coagulation factors (prothrombin, fibrinogen, proconvertin, accelerator globulin, Christmas factor, Stewart-Prower factor) and part of the natural basic anticoagulants (antithrombin, protein C, etc.). Hepatocytes participate in the formation of some fibrinolysis inhibitors; erythropoiesis regulators - erythropoietins - are formed in the liver. The glycoprotein haptoglobin, which forms a complex with hemoglobin to prevent its excretion by the kidneys, is also of hepatic origin. This compound belongs to the proteins of the acute phase of inflammation and has peroxidase activity. Ceruloplasmin, also a glycoprotein synthesized by the liver, can be considered an extracellular superoxide dismutase, which helps protect cell membranes; Moreover, it stimulates the production of antibodies. A similar effect, only on cellular immunity, has transferrin, the polymerization of which is also carried out by hepatocytes.

Another carbohydrate-containing protein, but with immunosuppressive properties, can be synthesized by the liver - b-fetoprotein, an increase in the concentration of which in the blood plasma serves as a valuable marker of some tumors of the liver, testes and ovaries. The liver is the source of most of the complement system proteins.

In the liver, the most active exchange of protein monomers - amino acids occurs: synthesis of non-essential amino acids, synthesis of non-protein nitrogenous compounds from amino acids (creatine, glutathione, nicotinic acid, purines and pyrimidines, porphyrins, dipeptides, pantothenate coenzymes, etc.), oxidation of amino acids with the formation of ammonia, which is neutralized in the liver during the synthesis of urea.

So let's consider are commonamino acid metabolic pathways. Common pathways for amino acid conversion in the liver include deamination, transamination, decarboxylation, and amino acid biosynthesis.

Deamination of amino acids. The existence of 4 types of amino acid deamination (cleavage of the amino group) has been proven (Appendix 17). The corresponding enzyme systems catalyzing these reactions were isolated and the reaction products were identified. In all cases, the NH 2 group of the amino acid is released in the form of ammonia. In addition to ammonia, deamination products include fatty acids, hydroxy acids and keto acids.

Transamination of amino acids. Transamination refers to reactions of intermolecular transfer of an amino group (NH2—) from an amino acid to a b-keto acid without the intermediate formation of ammonia. Transamination reactions are reversible and occur with the participation of specific aminotransferase enzymes, or transaminases.

Example of a transamination reaction:

Decarboxylation of amino acids. The process of removing the carboxyl group of amino acids in the form of CO 2. The resulting reaction products are biogenic amines. Decarboxylation reactions, unlike other processes of intermediate amino acid metabolism, are irreversible. They are catalyzed by specific enzymes - amino acid decarboxylases.

Neutralizationammonia in the body. In the human body, about 70 g of amino acids per day undergo breakdown, and as a result of deamination and oxidation reactions of biogenic amines, a large amount of ammonia, which is a highly toxic compound, is released. Therefore, the concentration of ammonia in the body should be kept low. The level of ammonia in the blood normally does not exceed 60 µmol/l. Ammonia must undergo binding in the liver to form non-toxic compounds that are easily excreted in the urine.

One of the ways to bind and neutralize ammonia in the body is the biosynthesis of glutamine (and possibly asparagine). Glutamine and asparagine are excreted in urine in small quantities. Rather, they perform a transport function of carrying ammonia in a non-toxic form. Glutamine synthesis is catalyzed by glutamine synthetase.

The second and main way of neutralizing ammonia in the liver is the formation of urea, which will be discussed below in the urea-forming function of the liver.

In hepatocytes, individual amino acids undergo specific transformations. Taurine is formed from sulfur-containing amino acids, which is later included in paired bile acids (taurocholic, taurodeoxycholic), and can also serve as an antioxidant, binding the hypochlorite anion, stabilizing cell membranes; activation of methionine occurs, which in the form S- adenosylmethionine serves as a source of methyl groups in the reactions of the end of creatine genesis, choline synthesis for choline phosphatides (lipotropic substances).

Biosynthesis of non-essential amino acids. Any of the non-essential amino acids can be synthesized in the body in the required quantities. In this case, the carbon part of the amino acid is formed from glucose, and the amino group is introduced from other amino acids by transamination. Alania, aspartate, and glutamate are formed from pyruvate, oxaloacetate, and b-ketoglutarate, respectively. Glutamine is formed from glutamic acid by the action of glutamine synthetase:

Asparagine is synthesized from aspartic acid and glutamine, which serves as an amide group donor; The reaction is catalyzed by asparagine synthetase. Proline is formed from glutamic acid. Histidine (a partially replaceable amino acid) is synthesized from ATP and ribose: the purine part of ATP supplies the -N=CH-NH- fragment for the imidazole cycle of histidine; the rest of the molecule is formed by ribose.

If there is no non-essential amino acid in food, cells synthesize it from other substances, and thereby maintain the full set of amino acids necessary for protein synthesis. If at least one of the essential amino acids is missing, protein synthesis stops. This is because the vast majority of proteins contain all 20 amino acids; therefore, if at least one of them is missing, protein synthesis is impossible.

Partially replaceable amino acids are synthesized in the body, but the rate of their synthesis is not sufficient to meet all the body's needs for these amino acids, especially in children. Conditionally essential amino acids can be synthesized from essential ones: cysteine ​​- from methionine, tyrosine - from phenylalanine. In other words, cysteine ​​and tyrosine are non-essential amino acids, provided there is sufficient dietary intake of methionine and phenylalanine.

1.1.4 Participation of the liver in vitamin metabolism

The participation of the liver in the metabolism of vitamins consists of the processes of deposition of all fat-soluble vitamins: A, D, E, K, F (secretion of bile also ensures the absorption of these vitamins) and many of the hydrovitamins (B 12, folic acid, B 1, B 6, PP etc.), synthesis of some vitamins (nicotinic acid) and coenzymes.

The liver is special in that it activates vitamins:

1. Folic acid is converted to tetrahydrofolic acid (THFA) with the help of vitamin C; Reduction involves the breaking of two double bonds and the addition of four hydrogen atoms at positions 5, 6, 7 and 8 to form tetrahydrofolic acid (THFA). It occurs in 2 stages of tissue with the participation of specific enzymes containing reduced NADP. First, the action of folate reductase produces dihydrofolic acid (DHFA), which, with the participation of a second enzyme, dihydrofolate reductase, is reduced to THFA:

1. Vitamins B 1 and B 6 are phosphorylated into thiamine diphosphate and pyridoxal phosphate, respectively. Vitamin B 6 (pyridoxine) is a derivative of 3-hydroxypyridine. The term vitamin B 6 refers to all three 3-hydroxypyridine derivatives that have the same vitamin activity: pyridoxine (pyridoxole), pyridoxal and pyridoxamine:

Although all three derivatives of 3-hydroxypyridine are endowed with vitamin properties, only phosphorylated derivatives of pyridoxal and pyridoxamine perform coenzyme functions. Phosphorylation of pyridoxal and pyridoxamine is an enzymatic reaction that occurs with the participation of specific kinases. The synthesis of pyridoxal phosphate, for example, is catalyzed by pyridoxal kinase:

Vitamin B 1 (thiamine). Its chemical structure contains two rings - pyrimidine and thiazole, connected by a methylene bond. Both ring systems are synthesized separately as phosphorylated forms, then unite through a quaternary nitrogen atom.

The conversion of vitamin B1 into its active form, thiamine pyrophosphate (TPP), also called thiamine diphosphate (TDP), involves the specific ATP-dependent enzyme thiamine pyrophosphokinase.

1. Some carotenes are converted to vitamin A under the influence of carotene dioxygenase. Carotenes are provitamins for vitamin A. There are 3 types of carotenes: b-, b- and d-carotenes, which differ from each other in their chemical structure and biological activity. β-carotene has the greatest biological activity, since it contains two β-ionone rings and, when broken down in the body, two molecules of vitamin A are formed from it:

During the oxidative breakdown of b- and g-carotenes, only one molecule of vitamin A is formed, since these provitamins each contain one beta-ionone ring.

4. Vitamin D undergoes the first hydroxylation on the way to produce the hormone calcitriol; In the liver, hydroxylation occurs at position 25. The enzymes that catalyze these reactions are called hydroxylases, or monooxygenases. Hydroxylation reactions use molecular oxygen.

5. Oxidized vitamin C is reduced to ascorbic acid;

6. Vitamins PP, B2, pantothenic acid are included in the corresponding nucleotides (NAD +, NAD + F, FMN, FAD, CoA-SH);

7. Vitamin K is oxidized to serve as its peroxide as a coenzyme in the maturation (post-translational modification) of protein coagulation factors.

The liver synthesizes proteins that perform transport functions in relation to vitamins. For example, retinol-binding protein (its content decreases with tumors), vitamin E-binding protein, etc. Some vitamins, primarily fat-soluble ones, as well as the products of their transformations, are excreted from the body as part of bile.

1.1.5 Participation of the liver in water-mineral metabolism

The participation of the liver in water-mineral metabolism is that it complements the activity of the kidneys in maintaining water-salt balance and is, as it were, an internal filter of the body. The liver retains Na +, K +, Cl -, Ca 2+ ions and water and releases them into the blood. In addition, the liver deposits macro- (K, Na, Ca, Mg, Fe) and micro- (Cu, Mn, Zn, Co, As, Cd, Pb, Se) elements and participates in their distribution to other tissues using transport proteins.

To accumulate iron, hepatocytes synthesize a special protein - ferritin. A water-insoluble iron-containing protein complex is detected in reticuloendotheliocytes of the liver and spleen - hemosiderin. Hepatocytes synthesize ceruloplasmin, which, in addition to the above functions, acts as a transport protein for copper ions. Transferrin, which, like ceruloplasmin, has polyfunctionality, is also formed in the liver and is used to transport only iron ions in the blood plasma. This protein is necessary for embryonic cell growth during liver formation. In the liver, the Zn ion is included in alcohol dehydrogenase, which is necessary for the biotransformation of ethanol. Selenium compounds entering hepatocytes are converted into Se-containing amino acids and, with the help of specific t-RNA, are included in various Se proteins: glutathione peroxidase (GPO), 1-iodothyronine-5’ - deiodinase, Se-protein P. The latter is considered the main transporter of this trace element. Deiodinase, found not only in the liver, ensures the conversion of the prohormone thyroxine into the active form - triiodothyronine. As is known, glutathione peroxidase is a key enzyme in antiradical defense. In the liver, sulfur included in amino acids is oxidized to sulfates, which in the form of FAPS (phosphoadenosylphosphosulfates) are used in the sulfonation reactions of GAGs, lipids, as well as in the processes of biotransformation of xenobiotics and some endogenous substances (examples of inactivation products are skatoxyl sulfate, indoxyl sulfate). The liver can serve as a temporary depot of water, especially during edema (the amount of H 2 O can be up to 80% of the organ’s mass).

1.1.6 Participation of the liver in pigment metabolism

The participation of the liver in the metabolism of pigments is manifested in the conversion of chromoproteins to bilirubin in the RES cells present in the liver, the conjugation of bilirubin in the liver cells themselves and the decomposition of urobilinogen absorbed from the intestine into non-pigment products.

Hemochromogenic pigments are formed in the body during the breakdown of hemoglobin (to a much lesser extent during the breakdown of myoglobin, cytochromes, etc.).

The initial stage of hemoglobin breakdown (in macrophage cells, in particular in stellate reticuloendotheliocytes, as well as in histiocytes of the connective tissue of any organ) is the rupture of one methine bridge with the formation of verdoglobin. Subsequently, the iron atom and the globin protein are split off from the verdoglobin molecule. As a result, biliverdin is formed, which is a chain of four pyrrole rings connected by methane bridges. Then biliverdin, being restored, turns into bilirubin, a pigment secreted with bile and therefore called bile pigment. The resulting bilirubin is called indirect (unconjugated) bilirubin. It is insoluble in water and gives an indirect reaction with the diazo reagent, i.e. the reaction occurs only after pretreatment with alcohol. In the liver, bilirubin combines (conjugates) with glucuronic acid. This reaction is catalyzed by the enzyme UDP-glucuronyltransferase, and glucuronic acid reacts in its active form, i.e. in the form of UDFGK. The resulting bilirubin glucuronide is called direct bilirubin (conjugated bilirubin). It is soluble in water and reacts directly with the diazo reagent. Most bilirubin combines with two molecules of glucuronic acid to form bilirubin diglucuronide. Direct bilirubin formed in the liver, together with a very small part of indirect bilirubin, is excreted with bile into the small intestine. Here, glucuronic acid is cleaved from direct bilirubin and its reduction occurs with the sequential formation of mesobilirubin and mesobilinogen (urobilinogen). From the small intestine, part of the resulting mesobilinogen (urobilinogen) is resorbed through the intestinal wall, enters the portal vein and is transported by the bloodstream to the liver, where it is completely broken down into di- and tripyrroles. Thus, normally mesobilinogen does not enter the general circulation and urine. The main amount of mesobilinogen from the small intestine enters the large intestine and here it is reduced to stercobilinogen with the participation of anaerobic microflora. The resulting stercobilinogen in the lower parts of the colon (mainly in the rectum) is oxidized to stercobilin and excreted in the feces. Only a small part of stercobilinogen is absorbed into the inferior vena cava system (first enters the hemorrhoidal veins) and is subsequently excreted in the urine (Appendix 18).

In most cases of liver disease, clinical tests clarify the nature of the lesion, based on the principles of syndromic diagnosis. The main pathological processes are combined into laboratory syndromes taking into account indicator tests: 1) cytolysis; 2) cholestasis (intra- and extrahepatic); 3) hepatodepression (hepatic cell failure, minor liver failure, failure of synthetic processes); 4) inflammation; 5) liver bypass surgery; 6) regeneration and tumor growth.

If a specific pathology is suspected, the main biochemical syndromes characteristic of this disease are taken into account. The standard functional examination program is taken as a basis, but at least two tests are examined for each case.

2.2.1 Cytolysis syndrome

It occurs when liver cells are damaged and occurs against the background of a pronounced violation of the integrity of the membranes of hepatocytes and their organelles, leading to the release of cell components into the intercellular space and blood. A cell undergoing cytolysis more often retains its viability, but if it dies, then we speak of necrosis.

In the case of hepatocyte pathology, enzymes released from them quickly end up in the blood plasma, since liver cells have direct contact with the interstitial and intravascular space; in addition, the permeability of the capillary walls in this organ is high.

The main biochemical changes are observed in the general pathways of catabolism. Oxidative phosphorylation suffers, as a result, the level of ATP drops, and the concentration of electrolytes changes. The imbalance of the latter is reflected in the degree of permeability of cell membranes. Long-term inhibition of ATP synthesis leads to energy deficiency, damage to the synthesis of protein, urea and hippuric acid, and changes in lipid and carbohydrate metabolism are observed.

An important role in the progression of this condition is played by lysosomes, which are destroyed due to the breakdown of membrane structures, and hydrolytic enzymes are released into the cytosol.

This laboratory syndrome is more common in acute viral hepatitis and other acute liver injuries (drug-induced, toxic), chronic active hepatitis, cirrhosis, and in rapidly developing and prolonged subhepatic jaundice.

2.2.2 Cholestasis syndrome

It is caused by shifts in the biliary function of liver cells with disruption of the formation of bile micelle and damage to the smallest bile ducts during intrahepatic cholestasis. Extrahepatic cholestasis is associated with mechanical obstructions to the normal flow of bile in the extrahepatic bile ducts.

With cholestasis syndrome, the activity of excretory enzymes increases, hypercholesterolemia is observed, the content of phospholipids, low-density lipoproteins (LDL), and bile salts increases. Hyperbilirubinemia is possible due to the bound fraction, the concentration of albumin decreases and the content of b, c- and g-globulins in the blood serum increases.

In cholestasis syndrome, determining the activity of alkaline phosphatase is of great diagnostic importance. , which splits off the remainder of phosphoric acid from its organic esters. This is a heterogeneous enzyme, which is represented by various isomers, since in the syndrome there is a maximum increase in alkaline phosphatase. Determining the activity of leucine aminopeptidase (LAP), which hydrolyzes N-terminal amino acid residues in proteins, is also important in cholestasis. In viral hepatitis, the activity of PAP, like aminotransferases, is increased (and can be 100 times higher than the upper limit of the physiological level).

In patients with cholestatic forms of liver damage, changes in pigment metabolism are recorded. In particular, hyperbilirubinemia due to its associated form is noted. Bilirubin, due to its hydrophilicity, appears in urine, giving it a dark color. On the other hand, there is no urobilin in the urine. A characteristic diagnostic sign is the presence of bile salts in the urine, which give it foaminess.

2.2.3 Hepatodepression syndrome (minor liver failure)

Mainly characterized by impaired synthetic function. With the syndrome, there is a decrease in cholinesterase activity in the blood serum, quantitative changes in blood glucose levels, a decrease in the content of total protein, especially albumin, hypocholesterolemia, a drop in the values ​​of blood coagulation factors II, V, VII, hyperbilirubinemia due to an increase in the contribution of the free fraction, changes in the parameters of stress tests ( bromsulfaleic according to Rosenthal-White, indocyanic-vofaverdine, ueverdine, antipyrine, galactose, caffeine).

In terms of diagnostic value, hepatodepressive syndrome is significantly inferior to cytolytic syndrome. However, biochemical indicators of this suffering play an important role in determining the severity of the disease and identifying severe hepatocellular failure, characteristic of fulminant forms. The most sensitive criteria are the antipyrine test, the content of proconvertin in the blood serum (normally 80-120%), which are reduced in the majority of patients with moderate hepatodepression syndrome. In everyday practice, tests of average sensitivity - prothrombin index and cholinesterase (ChE) activity in blood serum - are still widely used. Two types of ChE are detected in the human body: true acetylcholinesterase and pseudocholinesterase. The first hydrolyzes acetylcholine, and nerve tissue and red blood cells are rich in it, the second is synthesized mainly in hepatocytes and breaks down both choline and non-choline esters. ChE activity is an important laboratory diagnostic parameter characterizing the functional state of the liver. In this syndrome, ChE activity is inhibited. Tests in this group include determination of glucose levels . It has been established that the more severe the course of acute hepatitis, the more often hypoglycemia is observed . In acute liver failure, a decrease in the level of this monosaccharide in the blood develops in every fourth patient.

An imbalance in the protein spectrum of blood serum is characterized by hypoalbuminemia and an increase in globulin values ​​due to the g-fraction. In mild forms of hepatitis, the amount of proteins is not changed; in more severe forms, hyperproteinemia is noted against the background of a decrease in albumin levels. Secondary hypoalbuminemia in chronic liver damage (severe long-term viral hepatitis, cirrhosis) is an unfavorable prognostic sign. It can lead to a drop in the oncotic pressure of the blood plasma, the development of edema, and subsequently to ascites.

Lipid metabolism disorders, namely hypocholesterolemia, especially for the ether-bound fraction, are observed in acute viral hepatitis and malignant liver tumors. Determination of the fractional composition of cholesterol and individual lipoproteins (primarily HDL) in blood plasma is of greatest diagnostic importance.

Changes in pigment metabolism due to dysfunction of part of the liver cells are characterized by hyperbilirubinemia due to free bilirubin. Depending on the level of metabolic block, damage is distinguished at the following stages: in the active transport of the free fraction from the blood into liver cells and in the formation of bilirubin glucuronides in hepatocytes.

2.2.4 Inflammation syndrome

Caused by sensitization of cells of immunocompetent tissue and activation of the reticulohistiocytic system. The histological expression of this syndrome is lymphomacrophage infiltration of the portal tracts and intralobular stroma, that is, immune inflammation. Any immunological reaction unfolds through the interaction of T- and B-lymphocytes, macrophages, and neutrophils. In alcoholic liver damage, eosinophils are involved in the process. The inflammation syndrome is characterized by: hyperproteinemia due to an increase mainly in the proportion of g-globulins, an increase in the values ​​of immunoglobulins, especially IgG, IgM, IgA, changes in protein-sedimentary samples (thymol, sublimate, Veltman), the appearance of nonspecific antibodies to deoxyribonucleoproteins, smooth muscle fibers , mitochondria, microsomes. Colloid stability tests (thymol test, Veltman test, zinc sulfate test) are widely used in clinical diagnostic laboratories. The positive result of these tests is due to quantitative changes in the content of individual fractions (b-, c-, g-globulins) or a decrease in the albumin/globulin ratio. The most widespread is the McLagan test (thymol), which is clearly recorded in 90% of cases of acute viral hepatitis even in the pre-icteric stage of the disease, as well as in its anicteric form.

It is registered due to the development of powerful venous collaterals with the subsequent entry into the general bloodstream of a large amount of substances that would normally be transformed in the liver. These compounds include ammonium salts, phenols, amino acids (tyrosine, phenylalanine, tryptophan, methionine), short-chain fatty acids containing 4-8 carbon atoms (butyric, valeric, caproic and caprylic acids) and mercaptans . Accumulating in the blood in high concentrations, they become toxic to the central nervous system and threaten the occurrence of hepatic encephalopathy. Substances in this group also include endotoxins - lipopolysaccharides of gram-negative intestinal microbes.

In liver diseases, especially cirrhosis, the processes of deamination of amino acids and urea synthesis are disrupted. Amine nitrogen in the blood is not able to be neutralized in the liver (due to conversion to urea) and is sent to the general circulation, where its high concentration causes a toxic effect. “Ammonia” intoxication is one of the most important symptoms that stimulate the development of “liver” coma and encephalopathy.

2.2.6 Liver regeneration and tumor growth syndrome

Its indicator is the detection of large amounts of b-fetoprotein in the blood serum (8 times or more compared to the norm). Small increases in the level of this glycoprotein (1.5-4 times) are more common with increased regeneration, in particular with active cirrhosis of the liver. In general, the transition of the syndrome to chronic hepatitis, then to cirrhosis and cancer can be considered as a single pathological process.

Conclusion

The liver is one of the most important organs that support the vital functions of the body, since biochemical functions, including various metabolic reactions occurring in the liver, are the basis and connecting core of the general metabolism of substances. In addition, the liver performs specific functions, for example, it participates in digestion by secreting bile; filters blood with the formation of metabolic end products, which are subsequently excreted from the body; partially provides immunity by synthesizing blood plasma proteins.

In general, all liver functions lead to the maintenance of homeostasis, and a violation of at least one of them can lead to changes in the entire body, which means that liver diseases affect the condition of other organs and the body as a whole. Therefore, the course work examined the normal and pathological state of the liver and touched upon the basics of laboratory diagnostics, since knowledge of the skills to identify liver damage syndromes allows one to accurately diagnose and determine the cause of the disease in the future, which is very important at an early stage and makes it possible to prescribe appropriate treatment.

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Animals, plants, fungi, viruses, bacteria. The number of representatives of each kingdom is so large that one can only wonder how we all fit on Earth. But, despite such diversity, all living things on the planet share several basic features.

The commonality of all living things

The evidence comes from several basic features of living organisms:

• nutritional needs (energy consumption and its transformation within the body);
• breathing needs;
• ability to reproduce;
• growth and development throughout the life cycle.

Any of the listed processes is represented in the body by a mass of chemical reactions. Every second, hundreds of reactions of synthesis and decomposition of organic molecules occur inside any living creature, and especially a person. The structure, features of chemical action, interaction with each other, synthesis, decomposition and construction of new structures of molecules of organic and inorganic structure - all this is the subject of study of a large, interesting and diverse science. Biochemistry is a young, progressive field of knowledge that studies everything that happens inside living beings.

An object

The object of study of biochemistry is only living organisms and all the life processes occurring in them. Specifically, the chemical reactions that occur during the absorption of food, the release of waste products, growth and development. Thus, the basics of biochemistry are the study of:

1. Non-cellular forms of life - viruses.
2. Prokaryotic bacterial cells.
3. Higher and lower plants.
4. Animals of all known classes.
5. Human body.

At the same time, biochemistry itself is a fairly young science, which arose only with the accumulation of a sufficient amount of knowledge about the internal processes in living beings. Its emergence and isolation dates back to the second half of the 19th century.

Modern branches of biochemistry

At the present stage of development, biochemistry includes several main sections, which are presented in the table.

Chapter	Definition	Object of study
Dynamic biochemistry	Studies the chemical reactions underlying the interconversion of molecules within the body	Metabolites are simple molecules and their derivatives formed as a result of energy exchange; monosaccharides, fatty acids, nucleotides, amino acids
Static biochemistry	Studies the chemical composition inside organisms and the structure of molecules	Vitamins, proteins, carbohydrates, nucleic acids, amino acids, nucleotides, lipids, hormones
Bioenergy	Engaged in the study of absorption, accumulation and transformation of energy in living biological systems	One of the sections of dynamic biochemistry
Functional biochemistry	Study the details of all physiological processes of the body	Nutrition and digestion, acid-base balance, muscle contractions, conduction of nerve impulses, regulation of the liver and kidneys, action of the immune and lymphatic systems and so on
Medical biochemistry (human biochemistry)	Studies metabolic processes in the human body (in healthy organisms and in diseases)	Experiments on animals make it possible to identify pathogenic bacteria that cause diseases in humans and find ways to combat them

Thus, we can say that biochemistry is a whole complex of small sciences that cover the whole variety of the most complex internal processes of living systems.

Affiliated Sciences

Over time, so much different knowledge has accumulated and so many scientific skills have been formed in processing research results, breeding bacterial colonies and RNA, inserting known sections of the genome with given properties, and so on, that there is a need for additional sciences that are subsidiary to biochemistry. These are sciences such as:

• molecular biology;
• Genetic Engineering;
• gene surgery;
• molecular genetics;
• enzymology;
• immunology;
• molecular biophysics.

Each of the listed areas of knowledge has a lot of achievements in the study of bioprocesses in living biological systems, and therefore is very important. All of them belong to the sciences of the 20th century.

Reasons for the intensive development of biochemistry and related sciences

In 1958, Korana discovered the gene and its structure, after which the genetic code was deciphered in 1961. Then the structure of the DNA molecule was established - a double-stranded structure capable of reduplication (self-reproduction). All the subtleties of metabolic processes (anabolism and catabolism) were described, the tertiary and quaternary structure of the protein molecule was studied. And this is not a complete list of the most significant discoveries of the 20th century, which form the basis of biochemistry. All these discoveries belong to biochemists and science itself as such. Therefore, there are many prerequisites for its development. We can identify several modern reasons for its dynamism and intensity in its formation.

1. The basis of most chemical processes occurring in living organisms has been revealed.
2. The principle of unity in most physiological and energetic processes for all living beings has been formulated (for example, they are the same in bacteria and humans).
3. Medical biochemistry provides the key to treating a host of various complex and dangerous diseases.
4. With the help of biochemistry, it has become possible to approach the solution of the most global issues of biology and medicine.

Hence the conclusion: biochemistry is a progressive, important and very broad-spectrum science that allows us to find answers to many questions of humanity.

Biochemistry in Russia

In our country, biochemistry is as progressive and important a science as in the whole world. On the territory of Russia there are the Institute of Biochemistry named after. A. N. Bakh RAS, Institute of Biochemistry and Physiology of Microorganisms named after. G.K. Scriabin RAS, Research Institute of Biochemistry SB RAS. Our scientists have a great role and many merits in the history of the development of science. For example, the method of immunoelectropheresis, the mechanisms of glycolysis were discovered, the principle of nucleotide complementarity in the structure of the DNA molecule was formulated, and a number of other important discoveries were made. At the end of the 19th and beginning of the 20th centuries. Basically, not entire institutes were formed, but the department of biochemistry in some of the universities. However, soon there was a need to expand the space for studying this science due to its intensive development.

Biochemical processes of plants

The biochemistry of plants is inextricably linked with physiological processes. In general, the subject of study of plant biochemistry and physiology is:

• vital activity of a plant cell;
• photosynthesis;
• breath;
• water regime of plants;
• mineral nutrition;
• quality of the crop and the physiology of its formation;
• plant resistance to pests and unfavorable environmental conditions.

Implications for agriculture

Knowledge of the deep processes of biochemistry in plant cells and tissues makes it possible to increase the quality and quantity of crops of cultivated agricultural plants, which are mass producers of important food products for all mankind. In addition, the physiology and biochemistry of plants make it possible to find ways to solve problems of pest infestation, plant resistance to unfavorable environmental conditions, and make it possible to improve the quality of crop products.

Let's try to explain what functional biochemistry is. You've all heard the expression: “We are what we eat!” This is true in many respects, but we also breathe and absorb with the skin... The body is like a large production facility in which some technological processes take place: physical, chemical, electrical... This whole set is called metabolism or metabolism, or biochemical reactions. Thanks to metabolism, we live; it ensures the functioning of all organs and systems, their interaction with each other and with the external environment.

In science there are the concepts of “in vitro” and “in vivo”. For those who are not familiar with the terminology, let us explain: “in vitro” is what happens in a test tube, in a laboratory, under experimental conditions, and “in vivo” is what happens in living tissue, in the body, in the natural environment. These processes are not equivalent! There are biochemical reactions that cannot be reproduced either in a laboratory, or in a scientific research institute, or anywhere else, in a word! And in a living organism this reaction occurs very simply and naturally!!! This is the manifestation life! The task of functional biochemistry is to find out the characteristics of metabolism in each specific case. That is, to understand the features of interaction both with the external environment and the features of the course of biochemical processes within the body itself.

Metabolism is determined by a set enzymes. The set of enzymes is determined by the set genes. This is the official point of view of science. Every living thing has a “core” set of genes (core) that ensures viability. And the breakdown of these genes creates great difficulties in realizing life. And there are “options” (an additional set of genes) that provide our individuality: skin color, eye color, etc. These genes partly determine the characteristics of the interaction of a living organism with the external environment. And this is realized through our immunity. Everything that comes into contact with our body, is inhaled, absorbed, ingested - all this is primarily assessed by our immune system. And with its “permission” it interacts with the internal environment, can participate in metabolism, and so on.

A living organism is an open system, that is, to ensure its vital functions it must interact with the external environment. This property ensures the survival of the individual and the evolution of the species. If everything is ideal, then a person adapts well to changing conditions and can consume any product, any food, animal or plant origin. If not, then the person does not tolerate environmental changes well and part of the food becomes a toxin for the body.

And the functional approach to studying the metabolism of a particular person allows one to correct the “shortcomings” of interaction with the external environment, as well as the “difficulties” of internal metabolic processes. We must understand that the immune system plays a key role here. Substances that are not recognized as a source of nutrition (food) are perceived by the immune system as a foreign agent. As a result, the so-called reaction develops, which can manifest itself in one or more types of immunological reactions. If we are talking about an innate property of the organism (determined by the genome), then we can only adapt to it. Also, sometimes living tissue lacks some substances or components for full existence and ensuring all functions in the body. These conditions are called in medicine. In addition, there are compounds and substances that in most cases have an effect on living tissue. And their presence is extremely undesirable for the body. These include toxic metals, compounds of industrial or agricultural origin, toxins produced by organisms living inside us.

To diagnose these conditions, laboratory methods are used mainly, which make it possible to identify gross violations. Some of these research methods are currently being challenged. For example, a blood test does not reflect the actual level of vitamins and elements in tissues and in the body as a whole (with the exception of vitamin A). In our diagnostic work, we use standardized methods of applied kinesiology. This method allows you to identify fairly subtle and insignificant disorders at the metabolic (chemical) level, select a corrective substance and its dose. According to our data, in 91% of cases one or another correction of chemical processes is necessary, in addition to other methods (osteopathic, medicinal...).