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Last edited: 9/10/2021
CHOLESTEROL METABOLISM
Metabolism | Cholesterol Metabolism
OUTLINE
I) GENERAL
II) CHOLESTEROL SYNTHESIS
III) STRUCTURE
IV) FUNCTION
V) SUMMARY
VI) APPENDIX
VII) REVIEW QUESTIONS
Medical Editor: Uta Hüning
(3) Synthesis
Involves many steps
First steps are the same as in ketogenesis
(i) 1. step
Acetyl-CoA + Acetyl-CoA → Acetoacetyl-CoA + CoA
By: thiolase
I) GENERAL
Source of cholesterol:
o Dietary intake
o Endogenous synthesis
Important for:
o Bile salts
o Steroid hormones
o Lipoproteins
o Cell membrane component
II) CHOLESTEROL SYNTHESIS
Figure 3: First step of cholesterol synthesis
(ii) 2. step
Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA + CoA
HMG = 3-hydroxy-3-methyl glutaryl CoA
By: HMG-CoA synthase
(1) Where?
Liver (mainly)
All body cells
(2) When?
Recapitulation:
o Glucose → Pyruvate → Acetyl-CoA → Krebs cycle
→ ETC → ATP
Figure 4: Second step of cholesterol synthesis
(iii) 3. step
HMG-CoA → Mevalonate
By: HMG-CoA reductase (rate-limiting step), needs
NADPH
Figure 1: Glucose generates ATP
↑ Insulin (main anabolic hormone) stimulates breakdown
of glucose → ↑ Acetyl-CoA
o Ketone body synthesis (ketogenesis)
o Cholesterol synthesis
Figure 5: Third and rate-limiting step of cholesterol synthesis
Figure 2: Build-up acetyl-CoA enters ketone body synthesis or
cholesterol synthesis
CHOLESTEROL METABOLISM
Remember:
HMG-CoA → Mevalonate is one of slowest and most
regulated steps in entire body!
Because it is crucial to regulate how much cholesterol
we produce
Stimulated by: insulin
Inhibited by: cholesterol, glucagon
Drug: Lipitor (statin) inhibits this enzyme
METABOLISM: Note #1.
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(iv) Some step later:
III) STRUCTURE
Mevalonate → Isopentyl pyrophosphate
Isopentyl pyrophosphate = building block
Combining many molecules of Isopentenyl
pyrophosphate and its isomers
27 carbons: 4 rings + “antenna”
On 3rd carbon: usually alcohol group -> determines
difference between certain steroid hormones
Between 5th and 6th carbon: double bond
Figure 6: Mevalonate is converted to isopentyl pyrophosphate
(v) Many steps later:
Isopentenyl pyrophosphate → Isoprene unit
Figure 8: Structure of a cholesterol molecule
(vi) Many steps later:
IV) FUNCTION
Many isoprene units → Squalene
By: squalene synthase
(This can take up to 21 steps)
(1) Structural unit of cell membrane in every cell
Turns membrane less fluid, more rigid
Prevents phase transitions
Forms lipid raft by combining with glycosphingolipid
(important for ex. cell signalling)
(vii) Many steps later:
Squalene → 7-dehydrocholesterol
(viii) Many steps later:
7-dehydrocholesterol → cholesterol
Figure 9: Cholesterol as structural unit in cell membrane
(2) Steroid hormones
Testosterone, estrogen, corticosteroids (aldosterone,
cortisol), progesterone, …
(3) Bile salts
Cholic acid, deoxycholic acid
Important for emulsification of lipids (digestion)
(4) Lipoproteins
Figure 7: Isopentenyl pyrophosphate is converted into an
isoprene unit. Many isoprene unit condense into a molecule of
squalene which converts into 7-dehydrocholesterol and finally
cholesterol
Package cholesterol for sending to other tissues
Cholesterol → cholesterol-ester
By: ACAT enzyme, adds acyl group to 3rd carbon
On protein component: different apoproteins (depends on
type of lipoprotein)
o LDL: package cholesterol esters → transports
cholesterol to adrenal cortex, testis
o VLDL: cholesterol esters, TAG
o HDL: take up cholesterol from within arteries
Figure 10: Use of cholesterol
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METABOLISM: Note #1.
CHOLESTEROL METABOLISM
(2) Cholesterol Structure
V) SUMMARY
27 carbons: 4 rings + “antenna”
(1) Cholesterol synthesis
Involves many steps
Condition: ↑ Acetyl-CoA
Acetyl-CoA + Acetyl-CoA → Acetoacetyl-CoA
o By: thiolase
Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA
o By: HMG-CoA synthase
HMG-CoA → Mevalonate
o By: HMG-CoA reductase (rate-limiting step),
needs NADPH
(3) Cholesterol Function
Bile salts
Steroid hormones
Lipoproteins
Cell membrane component
Mevalonate → Isopentyl pyrophosphate
Isopentenyl pyrophosphate → Isoprene unit
Many isoprene units → Squalene
Squalene → 7-dehydrocholesterol
7-dehydrocholesterol → cholesterol (27 carbons)
VI) APPENDIX
Figure 11: Overview of cholesterol metabolism
VII) REVIEW QUESTIONS
1) Cholesterol synthesis is stimulated by:
a) Insulin
b) Glucagon
c) Cholesterol
d) Bile acids
2) Where does cholesterol synthesis mainly occur?
a) In muscles
b) In neural tissues
c) In the liver
d) In all body cells equally
3) Which enzyme catalyzes the most regulated step of
cholesterol synthesis?
a) Thiolase
b) HMG-CoA synthase
c) HMG-CoA reductase
d) Squalene synthase
CHOLESTEROL METABOLISM
4) Which is correct?
a) Many molecules of mevalonate condense to form an
isopentenyl pyrophosphate
b) Many molecules of isopentenyl pyrophosphate
condense to form an isoprene unit
c) Many isoprene units condense to form a squalene
d) Many molecules of squalene condense to form
cholesterol
5) Cholesterol’s functions does NOT include:
a) Bile salts
b) Cell membrane fluidity
c) Growth hormone
d) Lipoproteins
CHECK YOUR ANSWERS
METABOLISM: Note #1.
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