This document discusses cholesterol metabolism. It begins by defining different types of steroids like cholesterol, sterols, and steroid hormones. It then covers the structure, sources, functions, sites of biosynthesis, biosynthesis steps, regulation, and excretion of cholesterol. Key points include that the liver plays a central role in cholesterol homeostasis, cholesterol is synthesized from acetyl-CoA and is a precursor for other steroids, and HMG-CoA reductase is the rate-limiting step whose activity is regulated by feedback inhibition, phosphorylation/dephosphorylation, and competitive inhibitors like statins.

1. Cholesterol Metabolism
Dr Marwa Matboli
Dr Walaa Ibrahim
Dr Heba Morsi
Assistant professor of medical biochemistry
& molecular biology

3. Intended Learning Outcomes
By the end of this lecture , the
student should be capable of:
• List different types of Steroid
lipids.
• Describe the role of some
steroids.
• Identify the structure of some
steroids.
• Summarize the synthesis and
degradation of steroids.
• Explain the steps of bile
synthesis.
• Describe some abnormalities
in Steroid lipid metabolism

4. What are steroids?
Steroids
Sterols
(Cholesterol)
Steroid
hormones
Bile acids

5. Steroids Compounds with
19 C
Two CH3 (C19&18)
attached to
(C10&C13)
Steroids containing
hydroxyl groups are
often referred to as
sterols

6. Generally, there are 2 groups of sterols
Animal sterols
(cholesterol)
Plant sterols
(phytosterols)
As cholesterol in having OH at
C3
Are poorly absorbed by
humans
It is converted to Vit
D2(ergocalciferol) under the
skin by the action of UV

7. Structure Sources Function
Site of
Biosynthesis
Steps Regulation
Plasma
cholesterol
Excretion
Biochemical
derivatives of
cholesterol
Bile salts

8. Cholesterol is the
main steroid in the
body(27C)
A nonpolar
hydrocarbon body
The steroid nucleus
with an 8-
hydrocarbon side
chain at C-17
It has OH at carbon
3.

9. Sources of cholesterol
A little more than
half the cholesterol
of the body arises by
synthesis (about 700
mg/dl),
Only a little portion
of the body
cholesterol is derived
from diet
Vegetable Oil Contains
no cholesterol

10. The liver plays a central role in the
regulation of the body's
cholesterol homeostasis.
There is a critical balance between
the rate of cholesterol synthesis in
the body and rate of cholesterol
excretion.

11. • Cholesterol is widely distributed in all cells
of the body but particularly abundant in
nervous tissue.
• Precursor of all steroids in the body
(Steroid hormones & Bile Acids)

12. Structure Sources Function
Site of
Biosynthesis
Steps Regulation
Plasma
cholesterol
Excretion
Biochemical
derivatives of
cholesterol
Bile salts

13. Liver Intestine
Major sites for cholesterol biosynthesis

14. Substrates
Acetyl CoA
(From Pyruvate or FA
oxidation)
NADPH
(Cofactor)

15. Fates of Acetyl CoA
Krebs Cycle
Energy
Production
Well
Fed
FA synthesis
Cholesterol
Synthesis
Fasting
Ketone body
synthesis
Alternative
pathway for
energy production

17. There are 2 isoenzymes of HMG CoA
synthase
Cytosolic
Cholesterol
Synthesis
Mitochondrial
Ketogenesis

18. Cholesterol Biosynthesis

19. ATP dependent
decarboxylation
Condensation
(IPP x 6)
Cyclization

20. Synthesis of Mevalonate
by HMG-CoA reductase
Mevalonate is then activated by two successive phosphorylation
(catalyzed by kinases) yielding mevalonate 5-diphosphate
HMGR is the rate limiting step of cholesterol biosynthesis
Requires two NADPH as a cofactor
HMGR bound in the endoplasmic reticulum
HMG-CoA is then converted to mevalonate by HMG-CoA
reductase
mevalonate 5-diphosphate
2ATP
2ADP
kinases

21. Isopentenyl pyrophosphate (IPP)
Synthesis
Following the formation of
mevalonate 5-diphosphate
ATP-dependent decarboxylation
yields isopentenyl pyrophosphate
(IPP)
Which is an activated
isoprenoid molecule

22. Condensation of 6 activated isoprene unit to form
squalene(30C)
6

23. Squalene to
cholesterol
Squalene undergoes a
two-step cyclization to
yield lanosterol
catalyzed by hydroxylase
and cyclase
Conversion of lanosterol
to cholesterol involves
19 reactions, catalyzed
by enzymes in ER
membranes
A sequence of reactions
using molecular oxygen
and NADPH occurs

24. ATP dependent
decarboxylation
Condensation
(IPP x 6)
Cyclization

25. Structure Sources Function
Site of
Biosynthesis
Steps Regulation
Plasma
cholesterol
Excretion
Biochemical
derivatives of
cholesterol
Bile salts

26. 2.Long Term Regulation
(gene regulation)
1.Short Term Regulation
✓Feedback regulation
✓Covalent modification
✓Competitive inhibitors(Drugs)

27. Mevalonate (immediate product)
Cholesterol (End product)
Feedback
Inhibition

28. Covalent regulation
Glucagon &
Epinephrine
During fasting
Insulin
During well fed state
decreases its
activity by
increases its
activity by
phosphorylation
(action of AMPk
/cAMP-dependent protein kinase)
Dephosphorylation
(action of phosphatase)

29. They are used
to decrease
plasma
cholesterol
levels in
patients with
hypercholester
olemia
Statin drugs
are structural
analogs of
HMG-CoA
reversible
competitive
inhibitors of
HMG Co A
reductase
Statins
(Lovastatin,
Mevastatin,
Atorva Statin
etc.

30. 2.Long Term Regulation
(gene regulation)
Repression of HMG-CoA
reductase gene
(Controlled by the sterol
regulatory element binding
protein (SREBP) modulating its
expression)
Cholesterol (uptake by cells)