English Lectures / lipids 3 ENG
.pdfRegulation of cholesterol synthesis
2) Inhibition of the synthesis of HMG-CoA reductase. The end product of the metabolic pathway (cholesterol) reduces the transcription rate of the HMG-CoA reductase gene, thus inhibiting its own synthesis. In the liver, bile acids are actively synthesized from cholesterol, therefore bile acids (as the final products of synthesis) inhibit the activity of the HMG-CoA reductase gene. Since the HMG-CoA reductase molecule exists about 3 hours after synthesis, inhibition of the synthesis of this enzyme by the end product of the metabolic pathway (cholesterol) is an effective regulation.
Excretion of cholesterol and bile acids
•The route of excretion of bile acids simultaneously serves as the main route of excretion of cholesterol from the body.
•The structural basis of cholesterol - the cyclopentaneperhydrophenanthrene
ring - cannot be split into CO2 and water, like other organic components that come from food or synthesized in the body. Therefore, the bulk of cholesterol is excreted in the form of bile acids.
Excretion of cholesterol and bile acids
•A certain amount of bile acids is excreted unchanged, and some are exposed to the action of bacterial enzymes in the intestine. The products of their destruction (mainly secondary bile acids) are excreted from the body.
•Part of the cholesterol molecules in the intestine under the action of bacterial enzymes is restored by a double bond in ring B, resulting in the formation of 2 types of molecules - cholestanol and coprostanol, excreted in feces. From 1.0 g to 1.3 g of cholesterol is excreted per day from the body, the main part is removed with feces.
Hypercholesterolemia
•The concentration of cholesterol in the blood of adults is 200 ± 50 mg / dl (5.2 ± 1.2 mmol/L) and, as a rule, increases with age. Exceeding the normal concentration of cholesterol in the blood is called hypercholesterolemia. Hypercholesterolemia often develops due to the excess intake of cholesterol from food, as well as carbohydrates and fats.
Hypercholesterolemia
•Hypercaloric nutrition is one of the common factors for the development of hypercholesterolemia, since only acetyl-CoA, ATP and NADPH are needed for the synthesis of cholesterol. All these substrates are formed during the oxidation of glucose and fatty acids, so the excess intake of these food components contributes to the development of hypercholesterolemia. Normally, the intake of cholesterol from food reduces the synthesis of its own cholesterol in the liver, but with age, the effectiveness of regulation in many people decreases. Proper nutrition throughout life is the most important factor in the prevention of hypercholesterolemia.
Molecular mechanisms of the pathogenesis of atherosclerosis
The process begins with damage to the vascular endothelium, and damage can have various mechanisms. The most important mechanism is
•endothelial damage due to an altered structure of LDL, for example, as a result of activation of free radical LP in LDL;
•damage is provoked by free radicals formed in the process of metabolism or coming from outside.
During LPO in LDL, not only the structure of lipids themselves changes, but the structure of apoproteins is also disturbed. Oxidized LDL is captured by macrophages, which are overloaded with cholesterol and turn into “foamy cells” that penetrate the subendothelial space.
This leads to the formation of fat strips in the wall of blood vessels. At this stage, the vascular endothelium can maintain its structure. With an increase in the number of "foamy cells", vascular endothelium is damaged.
Molecular mechanisms of the pathogenesis of atherosclerosis
•When endothelial cells are damaged, platelets are activated. First, they secrete thromboxane A2, which stimulates platelet aggregation, which can lead to the formation of a thrombus in the area of atherosclerotic plaque.
•Secondly, platelets begin to produce a peptide, a plateletderived growth factor that stimulates proliferation of MMCs.
•MMCs migrate from the medial layer to the inner layer of the arterial wall and thus contribute to the growth of plaque. Further, the plaque sprouts with fibrous tissue; cells under the fibrous membrane are necrotic, and cholesterol is deposited in the intercellular space.
•At this stage, even cholesterol crystals form in the center of the plaque.
•In the last stages of development, the plaque is impregnated with calcium salts and becomes very dense.
•Most often, atherosclerotic plaques develop in the arteries of the myocardium, so the most common disease that develops as a result of atherosclerosis is myocardial infarction.
Biochemical basis for the treatment of atherosclerosis and prevention of myocardial infarction
•An important therapeutic factor that reduces the risk of developing hypercholesterolemia and atherosclerosis is the low-calorie and hypocholesterol diet. The intake of cholesterol with food should not exceed 300 mg / day.
•Cholesterol is a steroid of animal origin, so it enters the body when eating animal fats and fatty meat. Plant foods do not contain cholesterol, so in middle-aged and older people, it should form the basis of the diet.
Biochemical basis for the treatment of atherosclerosis and prevention of myocardial infarction
•Treatment and prophylactic factors include food fortification with polyenic fatty acids of the ω-3 family, which reduce the risk of thrombosis. Unsaturated fatty acids contribute to faster elimination of cholesterol from the body, although the mechanism of this phenomenon is not fully understood. At the same time, polyenoic acids have been shown to inhibit the synthesis of plateletderived growth factor and thus slow the development of atherosclerotic plaque.
•Vitamins C, E, A with antioxidant properties inhibit lipid peroxidation in LDL and support the normal structure of LDL lipids and their metabolism.
Biochemical basis for the treatment of atherosclerosis and prevention of myocardial infarction
•However, dietary corrective measures are inadequate in the treatment of severe hypercholesterolemia and atherosclerosis. The treatment of hypercholesterolemia is usually complex.
•One of the principles of treatment is the “opening” of the cycle of enterohepatic circulation of bile acids. To do this, use drugs such as cholestyramine - a polymer that adsorbs bile acids in the intestine, is excreted in the feces and thus reduces the return of bile acids to the liver. In the liver, the uptake of cholesterol from the blood increases for the synthesis of new bile acids.