CHOLESTEROL METABOLISM
Biological functions of cholesterol
1. In humans and animals, cholesterol is a major constituent of the cell membranes. Cholesterol
modulates physical properties of these membranes that in turn affect the function of
membrane proteins such as receptors and transporters. Experimental depletion of membrane
cholesterol cripples many cellular functions.
2. Cholesterol is the biosynthetic precursor of bile acids, which are essential for fat digestion.
3. Cholesterol is the precursor of all steroid hormones such as the sex hormones (estrogen,
testosterone, and progesterone) and corticosteroids (corticosterone, cortisol, cortisone, and
aldosterone
4. A percussor of calciferol (vitamin D).
Cholesterol also plays a major role in the pathogenesis of atherosclerosis and cardiovascular disease.
Cholesterol can both be synthesized endogenously (de novo synthesis -75%) and obtained from
the diet- 25% (especially meat, eggs and milk products). Our bodies have capacity to synthesize
enough cholesterol for our need.
Processes that determine the cholesterol balance
• intestinal uptake of dietary cholesterol de novo cholesterol synthesis (Regulation
of HMG-CoA reductase activity and levels).
• synthesis of steroid hormones from cholesterol
• synthesis of bile acids from cholesterol, and their biliary secretion biliary
secretion of surplus cholesterol in unmodified form
Cholesterol synthesis
Happens in the:
• liver kidney - adrenal cortex
• reproductive tissues - ovaries, testes, placenta
Cholesterol synthesis starts with acetyl-CoA being converted to hydroxymethylglutaryl-CoA
(HMG-CoA) in the cytosol. Like in the synthesis of fatty acids, cholesterol biosynthesis
therefore depends on the export of acetyl-CoA from the mitochondria.
All steps downstream of HMG-CoA occur in the smooth endoplasmic reticulum.
HMG-CoA reductase reduces HMG-CoA to mevalonate; this enzyme is the major target of
regulation in the entire pathway. Mevalonate is converted to various isoprene intermediates (C5,
CIO and CIS) which eventually get polymerized into a linear hydrocarbon molecule squalene
(C30). Squalene is cyclized to the first sterol intermediate, lanosterol, which is then converted
to cholesterol by several successive modifications.
, As with fatty acids, multiple steps in the cholesterol synthesis require NADPH.
1-1MG-CoA reductase
1-1MG-CoA
mevalonate
activated C 13 activated CIO activated C5
squalene (linear (230) Ianosterol cholesterol
o o HMG-
CoA
O OH
CoACoA
CoA-SH
CoA1-120 CoA-SH
O
2NADPH +
2H+
H20 + CoA-SH2NADP+
0-0-0
OH
C02 BADP isopentenyl- mevalonate
pyrophosphate
The reactions shown are catalyzed by thiolase (1), HMG-CoA synthase (2), HMG-CoA reductase
(3), mevalonate kinase, phosphomevalonate kinase (4), and diphosphomevalonate decarboxylase
(5). In the subsequent steps of the pathway, six molecules of isopentenyl-pyrophosphate are used
for the synthesis of one cholesterol molecule.
Biological functions of cholesterol
1. In humans and animals, cholesterol is a major constituent of the cell membranes. Cholesterol
modulates physical properties of these membranes that in turn affect the function of
membrane proteins such as receptors and transporters. Experimental depletion of membrane
cholesterol cripples many cellular functions.
2. Cholesterol is the biosynthetic precursor of bile acids, which are essential for fat digestion.
3. Cholesterol is the precursor of all steroid hormones such as the sex hormones (estrogen,
testosterone, and progesterone) and corticosteroids (corticosterone, cortisol, cortisone, and
aldosterone
4. A percussor of calciferol (vitamin D).
Cholesterol also plays a major role in the pathogenesis of atherosclerosis and cardiovascular disease.
Cholesterol can both be synthesized endogenously (de novo synthesis -75%) and obtained from
the diet- 25% (especially meat, eggs and milk products). Our bodies have capacity to synthesize
enough cholesterol for our need.
Processes that determine the cholesterol balance
• intestinal uptake of dietary cholesterol de novo cholesterol synthesis (Regulation
of HMG-CoA reductase activity and levels).
• synthesis of steroid hormones from cholesterol
• synthesis of bile acids from cholesterol, and their biliary secretion biliary
secretion of surplus cholesterol in unmodified form
Cholesterol synthesis
Happens in the:
• liver kidney - adrenal cortex
• reproductive tissues - ovaries, testes, placenta
Cholesterol synthesis starts with acetyl-CoA being converted to hydroxymethylglutaryl-CoA
(HMG-CoA) in the cytosol. Like in the synthesis of fatty acids, cholesterol biosynthesis
therefore depends on the export of acetyl-CoA from the mitochondria.
All steps downstream of HMG-CoA occur in the smooth endoplasmic reticulum.
HMG-CoA reductase reduces HMG-CoA to mevalonate; this enzyme is the major target of
regulation in the entire pathway. Mevalonate is converted to various isoprene intermediates (C5,
CIO and CIS) which eventually get polymerized into a linear hydrocarbon molecule squalene
(C30). Squalene is cyclized to the first sterol intermediate, lanosterol, which is then converted
to cholesterol by several successive modifications.
, As with fatty acids, multiple steps in the cholesterol synthesis require NADPH.
1-1MG-CoA reductase
1-1MG-CoA
mevalonate
activated C 13 activated CIO activated C5
squalene (linear (230) Ianosterol cholesterol
o o HMG-
CoA
O OH
CoACoA
CoA-SH
CoA1-120 CoA-SH
O
2NADPH +
2H+
H20 + CoA-SH2NADP+
0-0-0
OH
C02 BADP isopentenyl- mevalonate
pyrophosphate
The reactions shown are catalyzed by thiolase (1), HMG-CoA synthase (2), HMG-CoA reductase
(3), mevalonate kinase, phosphomevalonate kinase (4), and diphosphomevalonate decarboxylase
(5). In the subsequent steps of the pathway, six molecules of isopentenyl-pyrophosphate are used
for the synthesis of one cholesterol molecule.
