17' Cholesterol

1
17. Cholesterol lipoproteins
2
Cholesterol makes phospholipid membranes more
plastic
HO
cholesterol
3
Cholesterol associates with sphingolipids and
certain proteins to form rafts in the plasma
membrane
Lipids probably are more ordered in rafts than
elsewhere in the membrane because sphingolipids
usually have long, saturated fatty acid side
chains
4
Cholesterol serves as a precursor for steroid
hormones bile acids
5
Steroids are members of a large group of natural
products with structures based on isoprene
isoprene
cholesterol (27 carbons)
squalene (30 carbons)
ubiquinone-7 (35-carbon side chain)
b-carotene (40 carbons)
6
Experiments with radioactive tracers showed that
rats synthesize cholesterol and squalene from
acetate.
CH3CO2-
squalene
acetate
cholesterol
The labeling patterns in squalene and cholesterol
were similar, supporting the hypothesis that
squalene is an intermediate in cholesterol
biosynthesis.
7
The 5-carbon isoprenoid building block is
synthesized from acetate by way of a 6-carbon
intermediate, mevalonate
8
Mevalonate is synthesized from three molecules of
acetylCoAvia b-hydroxy-b-methylglutarylCoA
(HMG-CoA)
2 NADPH 2H
HMG-CoA reductase
2 NADP CoA-SH
key control point for cholesterol biosynthesis
9
Formation of isopentenyl pyrophosphate from
mevalonate consumes three molecules of ATP
ATP
ATP
mevalonate
ATP
isopentenyl pyrophosphate
10
Isopentenyl pyrophosphate tautomerizes to
dimethylallyl pyrophosphate, which can form a
relatively stable carbonium ion
allyl carbonium ion
11
Isopentenyl pyrophosphate and dimethylallyl
pyrophosphate combine to form geranyl
pyrophosphate
dimethylallyl- pyrophosphate
geranyl-pyrophosphate (10 carbons)
This creates a new allyl-pyrophosphate derivative
that can combine with a second molecule of
isopentenyl pyrophosphate to form farnesyl
pyrophosphate (15 carbons).
12
Two molecules of farnesylpyrophosphate condense
head-to-head to form squalene
13
Formation of squalene epoxide requires O2 and
NADPH
14
Cyclization of squalene epoxide zips up the
sterol rings
Protonation opens the epoxide and generates a
carbonium ion that reacts with the nearby CC
double bond, creating a new carbonium ion
theres more
15
The cyclase reaction continues
I wont expect you to remember these details.
16
Cholesterol biosynthesis is controlled primarily
by HMG-CoA reductase
b-Hydroxy-b-methyl-glutarylCoA
Phosphorylation inactivates HMG-CoA reductase
dephosphorylation activates it.
insulin
HMG-CoA reductase
glucagon
mevalonate
enzyme proteolysis
enzyme synthesis
Synthesis of the low-density lipoprotein (LDL)
receptor, which mediates uptake of lipoproteins
containing cholesterol, also is regulated.
Cholesterol or a derivative inhibits synthesis of
the receptor.
cholesterol
Cholesterol or a cholesterol derivative inhibits
synthesis and stimulates proteolysis of HMG-CoA
reductase.
17
Cholesterol prevents activation of transcription
of the HMG-CoA reductase gene
to nucleus
Cholesterol binds reversibly to a protein that
holds the Sterol Regulatory Element Binding
Protein (SREBP) in the ER membrane
In the absence of cholesterol, the proteins
separate and SREBP is cleaved by proteases
A soluble fragment of SREBP diffuses to the
nucleus, where it activates transcription
18
Lipoproteins carry cholesterol between the liver
and other tissues
This is a model. The structures of lipoproteins
are not known.
19
Cells take up low-density lipoproteins by
receptor-mediated endocytosis
20
Partial structures of Apolipoprotein-E and the
LDL receptor are known
Receptor-binding domain of Apo-E
Apo-E, the only protein in most LDLs, has 3
common alleles Apo-E3 is the most common form.
Apo-E4 has been linked to Alzheimers disease
elevated risk of heart disease. Apo-E2 binds
poorly to LDL receptors, is associated with
hyperlipidemia.
lipoprotein-binding portion of the LDL receptor
21
Low-density lipoproteins (LDL and VLDL) carry
cholesterol from the liver to other tissues
high-density lipoproteins carry it in the other
direction
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High levels of cholesterol in the blood can
result in atherosclerosis -- deposition of
cholesterol and other materials in the inner
walls of blood vessels
Coronary artery disease is the leading cause of
death in industrialized countries.

• Major risk factors
• high blood cholesterol (especially
• LDL cholesterol gt 100 mg/dL)
• smoking
• diabetes mellitus
• obesity
• physical inactivity

There usually are no symptoms until blood flow to
the heart is seriously compromised.
Individuals with defective LDL receptors have
exceptionally high plasma cholesterol (familial
hypercholesterolemia). Because cholesterol does
not enter their cells, HMGCoA reductase is not
regulated properly and cholesterol biosynthesis
remains switched on. If untreated, people with
this condition tend to die of atherosclerosis at
a young age.
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Inhibitors of HMG-CoA reductase (statins) are
used clinically to decrease cholesterol
biosynthesis
In addition to decreasing LDL cholesterol,
statins decrease the level of C-reactive protein
in the blood. C-reactive protein is a marker of
acute inflamation. Its role in atherosclerosis is
unclear. Ridker et al., New Engl. J. Med. 325 20
(2005) Nissen et al., New Engl. J. Med. 352 29
(2005)