“Pathologic chemistry of lipid’s metabolism”

The derangement of digestion and absorption of lipids

The reasons of derangement of digestion and absorption of lipids are next:

1. absence of bile;

2. derangement of entrance of pancreatic juice in a small intestine;

3. primary malabsorption;

4. receiving of a large amount of animal’s fats, for example mutton’s fat;

5. rapid intestinal peristalsis;

6. application of some drugs (for example, antibiotics – neomycin, chlortetracyclin);

7. hypocorticism;

8. excess of two-valent cations (calcium, magnesium) in the food and water. It promotes the formation of insoluble complexes of calcium and magnesium with FFA.

The derangement of digestion and absorption of lipids displays as fatty diarrhea.

A laboratory control includes the detection of: 1) total content of lipids in feces (in norm it is equal until 5g/day); 2) FFA of feces (in norm it is equal until 20mM/day); 3) stercobilin of feces (in norm it is equal 0.2-0.6g/day).

Biochemistry of starvation

In the starvation the level of glucose in blood plasma is decreased. It causes the stimulation of glycogenolysis and inhibition of biosynthesis of proteins. The storage of glycogen is finished in 12-24 hours of starvation and lipolysis and gluconeogenesis start. Thus, in 1-st week of starvation the lipolysis and gluconeogenesis dominate. The brain in this period can use the glucose and glucogenic aminoacids as energetic sources.

The 2-nd period of starvation beginns from 2-nd week. In this period the gluconeogenesis is decreased and the ketogenesis is increased. The brain beginns to use the ketone bodies as energetic source. Beside of ketogenesis the part of acetylCoA is used for synthesis of cholesterol therefore the hypercholesterolemia is observed.

The 3-rd period of starvation (terminal or period of decompensation) conform to loss of 40-50% of body weight with loss of 100% of reserve fat and almost of 97% fat of organs. This period is characterized by increase of cleavage of proteins and development of hypernitrogenemia.

Obesity and fat infiltration of a liver

Obesity is a pathologic excess of TAG in the body. It is an increase of body weight on 10% and more from normal weight.

There are 4 extent of obesity. 1-st extent conforms to excess of body weight 10-29% from normal one; 2-nd extent – 30-49%; 3-rd extent – 50-99%; 4-th extent – 100 and more %.

There are primary (constitutional) and secondary (symptomatic) obesity.

The key mechanism of the primary obesity consists in derangement of hormonal connection between adipose tissue and hypothalamus. In 1994 the hormone of adipocytes was opened. It is named leptin and it is secreted in full state (naurishing). Leptin goes in hypothalamus and joins with ventromedialis nucleus. It causes the feeling of full state. In the obesity the formation and secretion of leptin is decreased and this is accompanied by permanent hunger feeling. Thus, the primary obesity is a deficiency of leptin on dietary-hypodynamic phone.

If the content of TAG in the liver is more than 10% and the fatty drops are histologically revealed in more than half of hepatocytes, are said to be about steatosis of a liver (or fat infiltration of a liver).

The reasons are next: diabetes mellitus, obesity, hyperlipoproteinemia, abuse of alcohol, poisonings, starvation, hypovitaminosis, pregnancy, hereditary defects of oxidation of FFA.

The term “fat transformation of a liver) is referred to situation when the adipocytes appear in stroma of a liver.

The pathogenesis of its can be related with increase of entrance of lipids into hepatocytes; decrease of assembling and secretion of LPVLD; inhibition of oxidation of lipids in liver and combination of these factors. In this connection there are 2 main types of fat infiltrationof a liver: 1-st type results in increase of content of FFA on the blood plasma promoted by mobilization of fats from adipose tissue or hydrolysis of TAG of chylomicrons and LP. In this case the absorption and esterification of FFA by the liver are increased. It results in excess of TAG in liver and lack of LP are observed.

The 2-nd type is related with metabolic block of formation of LP. This derangement can be caused by: a) block of synthesis of apoproteins; b) block of formation of LP; c) insufficient formation of phospholipids; d) derangement of own secretory mechanism. The steatosis of a liver can be developed in the lack of proteins, PUFA, vitamins B3 and B6.

All compounds are being donators of CH3-group promote the secretion of LPVLD and oxidation of FFA. Hence, they are lipotropic factors. The main lipotropic factor is a choline. Vitamins B12, Bc, B6, Met, betain, inosit, pangamic acid, carnitine are referred to lipotropic factors too.

Vitamin PP, ethionine, guanidine acetate are antilipotropic factors. The cells of pancreatic ducts are secreted the lipocain which is lipotropic factor.

Biochemistry of atherosclerosis

There are 264 factors of risk of atherosclerosis. The main factors are next:

1. dislipoproteinemias: a) increase of LPVLD in normal value of LPLD; b) increase of LPLD in normal value of LPVLD; c) increase of LPLD and LPVLD;

2. hypertony;

3. smoking;

4. diabetes mellitus;

5. belonging to male (except men in age more 75).

One of factors of risk is a low hard water. One of the suitable theory of pathogenesis of atherosclerosis is the “theory of response to damage”: the big arteries are damaged due to the high pressure of blood stream on them. It occur when the disfunction of big arteries endotheliocytes is observed. The big arteries are naxt: abdominal, coronary, popliteal, femoral, tibialis, breast, carotis and arteries of the brain. There are initial (until lipid) phase, early lipid phase, late and complicated phases of atherogenesis. The initial phase is characterized by disfunction of endothelium of a big arteries. It creates a zones of increased permeability and stickness on the surface of endothelium. The retention of GAG, LPLD and LPVLD in these zones is observed.

The monocytes enter into intima and they are converted into macrophags. Stored LP are oxidated and interact with MDA and become unusual. They are scavengered by macrophags and macrophags are converted to foam cells.

The appearance of foam cells is a feature of transition of initial phase to early lipid phase. The peculiarities of earlu lipid phase are lipid spots and lines. This stage are very often in young men and kids. If the factors of risk continue to act the early phase transmits into late lipid phase which can be complicated. In this stage the atheromas, fibroids, fibroatheromes appear. In the area of atheroma the thrombocytes are activated and thromogenesis beginns to dominate in atheroma. The cells of intima are necrotized.

Bile stone’s disease (cholelithiasis)

Cholestrol in bile can exist in 3 phases. One phase is a mixed micelles containing cholestrol, bile acids and phosphatidylcholine. 2-nd phase is an out micellar liquid crystal cholesterol. 3-rd phase is a solid crystal cholesterol (precipitation). Liquid crystal phase is unstable: the cholesterol strives to transmit either in micelle or in precipitation. The decrease of synthesis (or secretion) of bile acids in increase of synthesis of cholesterol cab result in related excess of cholesterol. In these conditions a solid crystal phase of cholesterol is formed that is bile stones.

The cholestasis, cholecystitis promote the bile stone’s disease. The solubility of bile stones can increase the application of chenodeoxycholic acid (1 g/day). In this case the synthesis of cholesterol is decreased. The solution of bile stones lasts approximatelly half of year. This method is effective when the bile stones formed by cholesterol. The solubility of bilirubin doesn’t depend on bile acids.

The Simple Proteins Metabolism. The digestion of Proteins and absorption of amino acids. The rotting of Proteins and detoxification of products of rotting. The intermediate metabolism of Simple Proteins

Proteins of food and their importance. The concept of nitrogen balance

The peculiarities of Proteins metabolism:

1. Proteins carry out numerous functions in the body

2. They aren’t stored but there is a “crash” storage of proteins of blood plasma

3. Permanent renew of tissues, synthesis of hormones and enzymes demand permanent intake of Proteins with food

4. Fullvalue Proteins must be supplied through the diet. Fullvalue (complete) Proteins must contain all essential amino acids. There is a standard Protein which contains 31.4% of essential amino acids

Nitrogen balance is ration between nitrogen of Proteins which are absorbed and excreted. Nitrogen of food Proteins and Proteins of the body forms the pool of free amino acids (1/3 of food Proteins, 2/3 of Proteins of the body). Final products of Proteins Metabolism are excreted through urine (60%), feaces, skin and saliva. When nitrogen of food proteins is more then nitrogen of urine it is said to be about positive nitrogen balance. It is observed in childhood and pregnancy. It is also possible in some diseases, for example polycytemia, big non-malignant tumors, hypersecretion of Growth Hormone. When nitrogen of food Proteins is less then nitrogen of urine it is said to be about negative nitrogen balance. It is observed in aging, trauma, burns, cancer, starvation and other pathological processes which are accomplished by increased cleavage of proteins of the body.

The digestion of Proteins

Enzymes which hydrolyze Proteins belong to Peptide hydrolases (it is subclass of Hydrolases). Peptide hydrolases are divided into 2 subsubclasses – endopeptidases (Pepsin, Trypsin, Chymotrypsin, Elastase, Collagenase) and exopeptidases (Aminopeptidases, Carboxypeptidases and Dipeptidases). Endopeptidases hydrolyze Proteins to Peptides. Exopeptidases hydrolyze Peptides to free amino acids.

The digestion of Proteins begins in gaster, then in small intestine. Pepsin (enzyme of gaster) acts on proteins and hydrolyzes them to peptides.

Proteins of food stuffs are mainly hydrolyzed in small intestine under action of pancreatic enzymes such as Trypsin, Chymotrypsin, Elastase, Collagenase and Carboxypeptidase. This process also occurs under action of some intestinal peptidases such as aminopeptidases and dipeptidases.

Thus, the digestion of proteins results in formation of mixture of free amino acids in the lumen of small intestine.

The rotting of Proteins in large intestine and detoxification of products of rotting in liver

Beside of digestion food proteins undergo the rotting. There are some differences between digestion and rotting of proteins:

Digestion:

1. Gaster, small intestine

2. peptide hydrolases of gaster, pancreas, small intestine

3. digestion results in mixture of free amino acids

4. amino acids are absorbed in portal vein and used in the body

Rotting:

1. large intestine

2. enzymes of microbs of large intestine

3. rotting is a cleavage of amino acids

4. products of rotting are detoxified in liver and excreted through kidneys

There are 2 pathways of rotting: 1) decarboxylation; 2) oxidation of side chain

Diaminomonocarboxylic amino acids undergo the decarboxylation, for example, Ornithine and Lysine:

Ornithineputrescine+CO2

Lysinecadaverine+CO2

Putrescine and Cadaverine are also formed in dead body therefore they are named as ptomaines. Afterwards it turned out, that these substances aren’t toxic and can be excreted without detoxification through the kidneys.

Cyclic amino acids mainly undergo the oxidation of side chain:

Tryptophan+[O]ScatoleIndole

Tyrosine +[O]cresolphenol

Products of oxidation of side chain are called intestinal toxins. They enter the portal vein and undergo detoxification in liver by conjugation with sulfuric or glucuronic acids. Indole and scatole previously undergo the hydroxylation to Indoxyl and Scatoxyl, respectively:

Indoxyl+H2SO4Indoxylsulfuric acid

Scatoxyl+H2SO4 Scatoxylsulfuric acid

Indoxyl+glucuronic acid Indoxylglucuronic acid

Scatoxyl+glucuronic acid Scatoxylglucuronic acid

Thus, the detoxification of Indoxyl, Scatoxyl, Phenol and Cresol results in formation of coupled esterosulfuric and esteroglucuronic acids which are eliminated through the kidneys.

“Indican” is a Potassium or sodium salt of Indoxylsulfuric acid.

This index is equal 0.04g/l in urine. Increase of its is observed in enhance of rotting processes, for example intestinal obstruction, cleavage of intestinal tumor. Decrease of this index is observed in diseases of liver (decreased antitoxic function of liver).

The absorption of amino acids

Amino acids can be actively and passively absorbed. Active absorption of amino acids includes:

1. absorption with participation of ATP-ases (due to creature of gradient of concentration of Sodium ions);

2. absorption with participation of gamma-glutamyl-transpeptidase (GGT):

glutathioneglycylcysteyl+gamma-glutamyl (this reaction occurs in cytosol of intestinal cell. Then gamma-glutamyl exits from intestinal cell on its surface and there interacts with amino acid, forming dipeptide “gamma-glutamyl-transported amino acid”

gamma-glutamyl+amino acidgamma-glutamyl-amino acid (this reaction occurs under action of GGT). Formed dipeptide sinks into cytosol of intestinal cell and there is hydrolyzed to gamma-glutamyl and amino acid which is used in intestinal cell or exits in portal vein. Gamma-glytamyl joins with glycylcysteyl yielding glutathione again.