Cholesterol metabolism Structure of cholesterol OH is polar part The ring is non polar part Cholesterol ester (CE) is completely non polar.

Cholesterol metabolism

Structure of cholesterol

OH is polar partThe ring is non polar part

Cholesterol ester (CE) is completely non polar

Functions of cholesterol:

1- Enter in the structure of every cell (cell membrane).2- Gives vitamin D3 by UV radiation3- Gives bile acids and salts in liver and this is activated by thyroid hormone. 4- Give steroidal hormones (hormones of adrenal cortex and sex hormones).

Sources of cholesterol in our body:

Exogenous or Dietary source: it is present in egg yolk, meat,

burger, liver and brain.

Endogenous or from synthetic pathway in liver (mainly),

intestine, adrenal cortex, ovaries, testis and skin.

• Digestion occurs mainly in intestine

• Most dietary cholesterol is present in free form (not estrified) with 10-15%

present as cholesterol ester (CE, fatty acid attached to OH at C3). Since free

cholesterol is more absorbable (can penetrate the water layer surrounding the

enterocytes ), so all CE should be converted into free cholesterol

• Cholesterol esterase secreted in pancreatic juice acts on cholesterol ester giving

free cholesterol and fatty acids. Bile salts are necessary for activation of this

enzyme.

CE free Cholesterol + FA

I- Digestion and absorption of dietary cholesterol

esterase

In intestinal mucosa, the major

amounts of free cholesterol (about

80-90%) combine with acyl CoA

(active form of fatty acids) to form

cholesterol esters which

transported in blood with TAG,

phospholipids and apoprotein to

form lipoprotein chylomicron. The

enzyme that catalyzes cholesterol

esterification in mucosa is ACAT

(Acyl CoA: Cholesterol Acyl

Transferase).

II- Synthesis of cholesterol:

De novo synthesis of cholesterol occurs in all body cells but mainly

in the cytoplasm and ER of liver and intestine. Synthesis also occur

in adrenal cortex, ovary, testis, placenta, skin.

The precursor is acetyl CoA derived from oxidation of glucose in

mitochondrial matrix (as occur in FA synthesis) . SO in fed state

(high CHO diet) the excess acetyl CoA produced from glucose

oxidation is used for biosynthesis of both FA and cholesterol

- Acetyl CoA must be transported from mitochondria to cytoplasm as

citrate (as in fatty acid synthesis).then citrate is cleaved in the

cytoplasm by citrate cleavage system (exactly as occur in FA

synthesis)

Transport of acetyl CoA from mitochondria to cytoplasm:

Mitochondria:

OAA + Acetyl CoA

-CoA ↓ citrate synthase

Citrate

Inner mitochondrial membrane ↓ Citrate

+ CoA, ATP ↓ ATP citrate lyase

OAA + Acetyl CoACystosol

The process of cholesterol synthesis has these major steps:

1.Two molecules of acetyl CoA condense together to form

acetoacetyl CoA .

2.Acetoacetyl CoA condense with third molecule of acetyl CoA to

form hydroxymethyl glutaryl CoA ( HMG-CoA), the enzyme is

cytosolic HMG CoA synthase

3. HMG-CoA is reduced to mevalonate (6C), the enzyme is HMG

CoA reductase which is the key enzyme in the biosynthesis

4. Mevalonate is phosphorylated and decarboxylated to form the

isoprene unit [or called isopentenyl pyroposphate] (5C).

4. Two isoprene units condense to form geranyl pyrophosphate (10

C) which react with another 5C unit to from Farnesyl

pyrophosphate (15C)

5. Two molecules of farnensyl condense to form squalene (30 C)

which cyclise to form Lanosterol

6. Lanosterol is converted into cholesterol by series of reactions.

Mevalonate (6C) ↓phosphprylation and decaboxylation

Isoprene unit (5C) [or called isopentenyl pyroposphate]↓

Geranyl PP (10 C)↓

Feransyl PP (15 C)↓

Squalene (30 C) ↓cyclization

Lanosterol (30 C)↓ - 3CO2

Cholesterol (27 C)

cytoplasmic H MG-CoA synthase (different from that responsible for ketogenesis)

Cholesterol synthesis

Regulation of cholesterol synthesis: HMG- CoA reductase is the key (rate limiting) enzyme in the biosynthesis of cholesterol. It is regulated by:

1- Feed back inhibition by cholesterol: Cholesterol (the end product of the pathway) acts as feed back inhibitor of the pre-existing HMG –CoA reductase as well as inducing rapid degradation of the enzyme..

2- Drug inhibition: Statins such as atorvastatin (by Pfizer), lovastatin and simvastatin are drugs with a side chain structurally similar to HMG-CoA so competitively inhibit HMG-CoA reductase. They are used to decrease cholesterol levels in patients with hypercholesterolemia.

3- Diet: its activity activated by high CHO and fat diet and inhibited in starvation.

4- Hormonal regulation: insulin stimulate protein phosphatase enzyme which phosphorylates the enzyme and actives it (dephosphprylated form is the active form) antiinsulin hormons such as glucagon inactivate the enzyme. (it similar to regulation of acetyl Co A carboxylase enzyme in FA synthesi)

Degradation of cholesterol

Ring of sterol can’t be metabolized to CO2 & H2O in humans. The

excess cholesterol is eliminated from the body by conversion to bile

acids and bile salts (80-90%) or by secretion into bile (10-20%)

then to intestine for elimination.

Conversion of cholesterol into bile acids and bile salts:

80-90% of cholesterol is converted (oxidized) into bile acids then to

bile salts. This is activated by thyroxin hormone. So hypothyrodism

leads to increased cholesterol in blood.

Bile acids:

Two bile acids are synthesized in liver from cholesterol by the action 7-α hydroxylase enzyme and then further hydorxylation and oxidation of side chain, the produced bile acids are:

cholic acid and chenodeoxy cholic acid .

chenodeoxycholic acid and cholic acid are called primary bile acids.

OH

Synthesis of primary bile acids in the liver (for your knowledge)

OH

Formation of bile salts: Cholic acid and chenodeoxycholic acid

are conjugated in liver with either glycine or taurine (formed from

cysteine amino acid) forming glycocholic acid or taurocholic acid.

Bile salts are carried from the liver to gallbladder, where they are

stored for future use. Bile salts have more effective emulsifying

effect thean bile acids.

Enterohepatic Circulation of Bile Acids and Salts

• Cholic acid, chenodeoxycholic acid and their conjugates in liver

are secreted into intestine to help lipid digestion.

• In intestine, some bile salts are deconjugated to get bile acids.

Some primary bile acids are dehydroxylated by intestinal bacteria to

the secondary bile acids, identified as deoxycholic acid and

lithocholic acid.

• Entrohepatic circulation the bile salts

• 95 % of primary and secondary bile acids and salts are returned

to the liver, where they can be reconjugated with glycine or taurine.

• 5% of bile acids are lost in the feces

Functions of bile salts in fat metabolism:

1. their synthesis and subsequent excretion in the feces represent the

only significant mechanism for the elimination of excess cholesterol.

2. Bile salts and phospholipids solubilize cholesterol in the bile,

thereby preventing the precipitation of cholesterol in the gallbladder.

So deficiency of bile salts leads to cholesterol gallstones.

3. they facilitate the digestion of dietary triacylglycerols by acting as

emulsifying agents that render fats accessible to pancreatic lipases.

4. Activate pancreatic lipase (steapsin) and cholesterol esterase

Disturbances in cholesterol metabolism:

Plasma cholesterol: normal cholesterol level in blood is 150-250 mg/dL (average 200 mg/dL). Plasma cholesterol is derived mainly from liver and intestine.

Hypercholesterolemia: i.e increased cholesterol level in blood than 250 mg/dL:

Causes:1- Hypothyrodism: lead to decreased conversion of cholesterol into bile acids and decreased mobilization of cholesterol from blood to tissues.

2- Diabetes: due to increased absorption of dietary cholesterol

3- Diet rich in carbohydrates, and fats: increase the synthesis of cholesterol in liver due to: a - Increased the activity of the key enzyme (HMG-CoA reductase). b - Formation of excess acetyl CoA (from fats and CHO) than the requirements of kreb’s cycle.c- insulin secreted after CHO diet will activate the key enzyme (dephosphorylate it)

4- High cholesterol in diet

Hypocholesterolemia: decrease of cholesterol level in blood below 150 mg/dL:

1- Hyperthyrodism: ↑ thyroid hormone→

a- ↑ oxidation of cholesterol into bile salts.

b- increase mobilization of cholesterol from blood to tissues.

2-Starvation: inhibits cholesterol synthesis by decreasing HMG-CoA

reductase.

3- Estrogens: decrease cholesterol and prevent atherosclerosis, so,

coronary heart disease rarely occurs in females during reproductive

period of life.

Study question:

High carbohydrate diet may lead to all of the following

EXCEPT:

a) release of insulin which inactivate HMG CoA reductase

b) Hypercholesterolemia

c) Over synthesis of fatty acids and TAG

d) Increased synthesis of acetyl CoA carboxylase