Regulation of cholesterol synthesis

Cholesterol biosynthesis is controlled by the rate limiting enzyme HMG CoA reductase.

1. Allosteric regulation. Cholesterol and bile acids in liver inhibit HMG-CoA reductase.

2. Repression of synthesis of HMG-CoA-reductase by cholesterol. It is feedback control.

3. Hormonal regulation. Glucagon deactivates, and insulin activates HMG-CoA reductase. The hormons exert their influence through cAMP by a series of reactions. The dephosphorylated form of HMG-CoA reductase is active, phosphorylated form is inactive. Thus, rate of cholesterol synthesis varies with the change of absorptive and post-absorptive states.

4. Rate of HMG-CoA-reductase synthesis in liver is subject to circadian rhythms: it is maximum at midnight, and it is minimum in the morning.

Cholesterol esters metabolism

Cholesterol esterification occurs in cells under the action of acyl-CoA cholesterol acyltransferase (АCAT):

Acyl-CoA + Cholesterol НS-CоА + Acylcholesterol

In cells linoleil cholesterol is mainly formed. Esters are mainly located in cytosol as lipid drops. Formation of esters can be considered as the mechanism for removing excess cholesterol from the membranes and as the mechanism for storing cholesterol in cells. Esterase enzyme hydrolyzes cholesterol esters and mobilizes cholesterol:

Acylcholesterol + Н₂О Fatty acid + Cholesterol

Synthesis and hydrolysis of esters occur especially actively in cells of adrenal glands cortex.

In blood lipoproteins formation of esters occurs with the help of lecithin cholesterol acyltransferase (LCAT), catalyzing the transfer of the acyl residues from lecithin to cholesterol. LCAT is formed in liver, secretes in blood and joins lipoproteins. LCAT is most active in HDL where it is localized in the surface layer. Cholesterol esters which are formed here are hydrophobic. They are dipped into lipid kernel. In phospholipid monolayer the place for cholesterol is freed which can be filled by cholesterol from cellular membranes or from others lipoproteins. Thus, HDL as a result of LCAT action is cholesterol “trap”.

Synthesis of bile acids

Part of cholesterol is converted to bile acids in the liver. The bile acids are amphipathic because contain both polar and non-polar groups. There are hydroxyl groups in the steroid nucleus and a side chain. They serve as emulsifying agents. Primary bile acids (chenodeoxycholic and cholic) are formed from cholesterol in hepatocytes. The step catalyzed by 7 α-hydroxylase is the rate limiting reaction. After bile acids excretion into intestine the secondary bile acids are formed from them under the action of intestinal flora enzymes - lithocholic and deoxycholic acids. They are absorbed from intestine, enter the liver with the blood of portal vein, and then into bile. In bile they are conjugated with glycine or taurine and form sodium or potassium salts (bile salts). Concentration of bile acids in bile is nearly 1%.

The main part of bile acids participates in enterohepatic circulation. The small part of bile acids - about 0,5g daily - is excreted with feces. It is compensated by the synthesis of new bile acids in liver.

The cholesterol in the human body contains endogenous cholesterol synthesized in liver, and exogenous cholesterol which enters with food. Cholesterol is removed mainly through intestine. Into the intestine it comes with food and from the liver as part of bile. Removal of cholesterol occurs also in the form of bile acids.

In a stationary state:

(Cholesterol_endog + Cholesterol_exog) = (Cholesterol_excr + Bile acids_excr)

If this balance is broken the concentration of cholesterol in tissues and in blood is changed. Hypercholesterolemia is increasing of cholesterol concentration in blood. In this case the probability of atherosclerosis and cholelithiasis increase.