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).