Cholesterol biosynthesis formation of bile salts and steroid hormones B.Pharmacy 2nd Semester 2022 (2021-2022) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

Cholesterol
• Cholesterol is exclusively found in animals hence called as animal sterol. Almost all
nucleated cells can synthesize cholesterol. It is widely distributed in our body.
• Brain and nervous tissues of human body contains large quantities of cholesterol. Liver ,
kidney and skin also contain fairly good amounts of cholesterol.
• The total quantity of cholesterol in an adult man weighing 70kg is about140g.
• Our body has the capacity to produce 1g/day.
• Per day about o.3 g of cholesterol is obtained from diet .Dietary cholesterol is obtained
only from animal foods like milk, meat, liver and eggs etc.
• The normal level of cholesterol in blood is 140-250mg/dl.
Physical properties: cholesterol is a white waxy like liquid associated with fats.
✓ It contains a special ring called cyclopentanoperhydro-phenanthrene.
✓ It is a amphipathic in nature because of the presence of both hydrophilic and
hydrophobic regions in its structure.
✓ Cholesterol is insoluble in water and is soluble in chloroform and other fat
solvents.
Biological functions of cholesterol:
▪ Cholesterol serves as structural component of cell membrane.
▪ Bile acids are produced from cholesterol in liver.
▪ Cholesterol serves as a precursor for the synthesis of steroid hormones, vit-D and
other steroids including bile salts.
▪ Cholesterol is a poor conductor of heat and electricity and has high dielectric constant.
So, cholesterol acts as an insulator.
▪ Cholesterol in brain and nervous tissue functions as an insulating covering material on
several structures which can generate and transmit electrical impulses.
▪ Cholesterol aids in the permeability of the cells.
▪ It transports fat to liver in the form of cholesterol ester for oxidation.
Clinical significance of cholesterol:
Abnormality in cholesterol metabolism leads to the accumulation of cholesterol in
blood that in turn leads to atherosclerosis and myocardial infarction.
Cholesterol biosynthesis
✓ About 1g of cholesterol is synthesized per day in adults. Liver is the principal organ for
its synthesis.
✓ About 50% of cholesterol synthesized in liver. Other tissues that synthesize
cholesterol are skin, intestine, gonads, adrenal cortex and kidney.
✓ It is interesting that brain of new born can synthesize cholesterol but adult brain
cannot synthesize cholesterol.
✓ The enzymes needed for cholesterol biosynthesis are located in cytosol and
microsomal fractions of the cell.
✓ Acetyl CoA is the starting material for cholesterol biosynthesis. All carbon atoms of
cholesterol are derived from acetyl CoA.
Biosynthesis of cholesterol involves following steps:
STEP1: Condensation
Two molecules of acetyl CoA undergo condensation to give acetoacetyl CoA. The enzyme involved in
this reaction is cytoplasmic aceto-acetyl CoA synthase.
STEP2: Production of HMG CoA
Acetoacetyl CoA reacts with one more molecule of acetyl CoA in presence of HMG CoA synthetase to
produce HMG CoA.
STEP3: Formation of mevalonate
The synthesis of mevalonate is a committed step in cholesterol biosynthesis. The enzyme catalyzing this
irreversible step is HMG CoA reductase. This is the important control step in cholesterol synthesis.
STEP4: Production of isoprenoid units
Mevalonate is converted to 3-phospho-5-pyrophospho mevalonate by 3 consecutive phosphorylation.
This labile intermediate loses CO2 and pi, yielding 3-isopentenyl pyrophosphate (IPP).
IPP further undergoes isomerisation to dimethylallyl pyrophosphate (DPP).This isomerisation reaction is
catalysed by the enzyme isopentenylpyrophosphate isomerase. Both IPP and DPP are the activated
isoprenoid units.
STEP5: Synthesis of squalin
Condensation of all 5C units yields 30C compound, squalin.
DPP (5C) + IPP (5C) = GPP (Geranyl pyrophosphate)(10C)
GPP (10C) + IPP (5C) = Farnesyl pyrophosphate (FPP)(15C)
FPP (15C) + FPP (15C) = Squalin (30C)
STEP6: Conversion of squalin to cholesterol
Squalin now undergoes oxidation and cyclization by epoxidase and cyclase,using molecular oxygen and
NADPH to form squalin epoxide and lanosterol .formation of cholesterol from lanosterol is a multistep
process involves 19 enzymatic reactions. The most important reactions are:
a) Reduction of carbon atoms from 30 to 27 carbon atoms
b) Removal of 2 methyl groups from C4 and One methyl group from C14.
c) shifting double bond from C8 to C5
d) Reduction in the double bond present between C24 and C25.

Regulation of cholesterol synthesis:
HMG CoA reductase is the rate limiting enzyme by which biosynthesis of cholesterol is regulated.
• Cholesterol itself inhibits the enzyme HMG CoA reductase by feed-back inhibition.
• Fasting/ starvation inhibit the enzyme and decreases cholesterol synthesis.
• Fasting diverts the enzyme for the synthesis of ketone bodies. High fat diet can accelerate the
cholesterol synthesis.
• Increased dietary intake reduces endogenous biosynthesis of cholesterol by reducing the activity
of HMG CoA reductase.
• Insulin and thyroid hormones increases HMG CoA reductase activity .where as glucagon and
corticosteroids decreases the activity of the HMG CoA.
Formation of bile acids:
Bile acids are synthesized in the liver from cholesterol. Bile acids contain 24 carbon atoms, all of them
have alpha- oriented hydroxyl groups at the position 7.
Reactions involved in the biosynthesis of bile acids are:
1. Hydroxylation of cholesterol at 3,7,12 positions: this is the rate limiting step catalysed by 7-
alpha –hydroxylase.
2. Removal of 3C unit, to make it 24C
3. Formation of bile salts: the primary bile acids are now conjugated with glycine or taurine to
form bile acids. They are glyco-cholic acid,taurocholic acid, glyco chenodeoxycholic acid and
tauro chenodeoxycholic acid. The major conjugated bile acid is glycocholic acid. Conjugation
adds more polar groups and increases the efficiency of bile acids as surfactants.
The conjugated bile acids are excreted through bile. In the bile they exist as bile salts (sodium or
potassium salts of conjugated bile acids.
4. Secretion into intestinal canal.
5. Formation of secondary bile acids/bile salts: primary bile acids acted upon by intestinal bacteria
which results in deconjugation. The deconjugated bile acids are then converted to secondary
bile acids by removal of the alpha hydroxyl group at position 7.
Cholic acid then converted to deoxy cholic acid and chenodeoxycholic acid to lithocholic acid.


Functions of bile salts:
• They facilitate digestion of lipids by forming molecular aggregates called micelle.
• Bile salts acts as biological detergents that enable the body to excrete cholesteroland
potentially toxic compounds( eg, bilirubin ,drug metabolites)
• The function of bile salts in duodenum is to solubilize ingested fat and fat soluble vitamins,
facilitating their digestion and absorption
• Control blood sugar levels.
• Improves metabolism.
• Antibacterial activity
• Antiviral activity
• Aid in digestion of gallstones.
• Stimulates breakdown o brown fat.
• Alkaline PH of the bile is to neutralize the acidity of the gastric juice.
• Bile salts are the efficient surfactants and detergents
• Bile is responsible for the excretion of certain drugs which are detoxified by liver.
• It helps in regulating the body cholesterol.
• Bile is the only route for the excretion of bilirubin which is the end product of haeme
catabolism.
Enterohepatic circulation of bile salts:
• About 15-30gm of bile salts reaches the intestine everyday and 250-300mg is excreted
through faeces and rest is absorbed by ileum which den reaches liver and re-excreted
through bile. This is referred as Enterohepatic circulation.
• When bile acid binding resin (cholestyramine ) is given, the reabsorption of bile acids is
inhibited. Hence more cholesterol gets converted to bile acids and cholesterol is decreased.
Conversion of cholesterol to steroid hormones :
Cholesterol is the precursor of the five major classs of steroid hormones: progestagens,
glucocorticoids , mineralocarticoids, androgens and estrogens.
Steroid hormones are the derivates of cholesterol that are synthesized by a variety of tissues,most
prominently adrenal gland and gonads.
➢ Biosynthesis of steroid hormones requires a battery of oxidative enzymes located in both
mitochondria and endoplasmic reticulum.
➢ The rate limiting step in this process is the transport of free cholesterol from cytoplasm into
mitochondria.
➢ Within mitochondria, cholesterol is converted to pregnenolone by an enzyme CYP11A1.
➢ pregnenolone itself is not an harmone, but is the immediate precursor for the synthesis of all
steriod hormones.