Cholesterol Metabolism

Sources of body cholesterol

Little more than 50% synthesized by the

body

The rest derived from diet.

Function of body cholesterol

Precursor of all other steroid in the body:

corticosteroids, sex hormones, bile acids and vitamin D.

Essential component of plasma membrane and other

cell membranes and the outer layer of plasma

lipoproteins (amphipathic lipids).

Transport form and storage

form of cholesterol

Transport form in plasma

Free cholesterol in lipoproteins.

Storage form in most tissue

cholesterol ester

Biosynthesis of cholesterol

Site:

Extramitochondrial (endoplasmic reticulum + cytosol)

• In liver 10%

• In intestine 10%

• Significant amount in the skin

• All tissues containing nucleated cells.

The enzymes involved in cholesterol biosynthesis are present

in cytosol and microcosms of the cell.

– The liver main source of plasma cholesterol

intestine also participates.

– The liver the principle organ, which removes

cholesterol from blood.

steps

• Acetyl-CoA is the source of all carbon atoms in cholesterol.

• Initial reactions involve the formation of HMG CoA.

• HMG CoA reduced to mevalonic acid (C6) is a reaction requiring NADPH+H+ and enzyme HMG CoA reducates.

• Mevalonic is dehydrated and decarboxyalted to isoprenoid units.

O O O

II II II

CH3 – C – CH2 – C ~ SCoA + CH3 – C ~ SCoA

Aceto Acetyl CoA Acetyl CoA

OH O

I II

HOOC-CH2 – C – CH2 – C ~ SCoA

I

CH3

HMG CoA

HMG CoA synthetase

OH O

I II

HOOC-CH2 – C – CH2 – C ~ SCoA

I

CH3

HMG CoA

OH

I

HOOC-CH2 – C – CH2 – CH2OH

CH3

Mevalonic Acid

HMG CoA reductase

2 NADPH2

2 NADP

CoA SH

OH

I

HOOC-CH2 – C – CH2 – CH2OH

CH3

Mevalonic Acid

CH2 = C – CH2 – CH2OH

CH3

Isoprene Unit

H2O

CO2

steps

6 isoprenoid units isomerized in a head to tail fashion to produce squalene (C30).

Squalene ring closure lanosterol

loses 3 CH3 groups zymosterol

shift of double bonds desmosterol

reduced cholesterol.

CONTROL OF CHOLESTEROL

BIOSYNTHESIS:

HMG CoA reductase is the key enzyme,

1) dephosphorylated active .

2) phosphorylated inactive

1-HMG CoA reductase is activated by insulin and thyroid

hormones and by feeding carbohydrate.

2-HMG CoA reductase is inhibited by glucagon, therefore its

activity decrease during starvation, as starvation directing acetyl-

CoA to the formation of ketone bodies.

3-Cholesterol feeding inhibits liver HMG CoA reductase.

4-Bile salts inhibit the intestinal HMG CoA reductase

CHOLESTEROL TRANSPORT:

Cholesterol is transported between tissues in plasma lipoproteins.

Cholesterol ester in the diet is hydrolyzed to free cholesterol, which mixes

with dietary free cholesterol and biliary cholesterol before absorption from

the intestine. After absorption it mixes with cholesterol synthesized in

intestine and is incorporated into chylomicrons. About 80-90% of the

cholesterol absorbed are esterified with long chain FA in the intestinal

mucosa, when chylomicrons react with lipoproteins lipase to form

chylomicron remenants only 5% of cholesterol is lost, chylomiron

remenant enter liver by binding with receptor that recognize apo E in

remenant chylocimron where it is metabolized by hepatic lipase and free

cholesterol is librated.

VLDL formed in the liver transport cholesterol to plasma, most of

cholesterol in VLDL is retained in IDL that is taken by the liver or

converted to LDL, which in turn is taken up by LDL receptor in liver

and extra hepatic tissues.

HDL removes free cholesterol from extra-hepatic tissues and

esterifying it using plasma enzyme LCAT. Cholesterol esters

accumulate in core of HDL, transferred to IDL and other

lipoprotein or HDL carries cholesterol ester to liver by binding

with HDL receptor that recognize apo A1 in HDl, and hydrolyzed in

liver. The released cholesterol either enters in the structure of

other lipoproteins, bile salts, or excreted in bile.

N.B:

Mainly cholesterol is transported in LDL in the form of cholesterol

esters more than free cholesterol.

Blood Cholesterol:

• Total cholesterol in plasma is normally between 140-300 mg/dl, 2/3 of

this is esterified with long chain FA (linoleic).

• Cholesterol esters are continually hydrolysed in liver and resynthesized

in plasma, this occurs by transfer of unsaturated FA in position 2 of

lecithin (HDL) under the effect of LCAT.

• Cholesterol is present in all the lipoproteins but in fasting more than

60% is carried in β lipoproteins (LDL).