Cholesterol, which is transported in the blood in lipoproteins because of its absolute insolubility in water, serves as a stabilizing component of cell membranes and as a precursor of the bile salts and steroid hormones. As a major component of blood lipoproteins, cholesterol can appear in its free, unesterified form in the outer shell of these macromolecules and as cholesterol esters in the lipoprotein core

1. 12/23/2023 1

2.  Cholesterol : is one of the most highly recognized molecules in
human biology, in part because of a direct relationship between its
concentrations in blood and tissues and the development of
atherosclerotic vascular disease .
 Cholesterol, which is transported in the blood in lipoproteins
because of its absolute insolubility in water, serves as a stabilizing
component of cell membranes and as a precursor of the bile salts
and steroid hormones.
 As a major component of blood lipoproteins, cholesterol can appear
in its free, unesterified form in the outer shell of these macromolecules
and as cholesterol esters in the lipoprotein core
12/23/2023 2

3.  Cholesterol is obtained from the diet or synthesized by a
pathway that occurs in most cells of the body, but to a greater
extent in cells of the liver and intestine.
 The precursor for cholesterol synthesis is acetyl CoA, which
can be produced from glucose, fatty acids, or amino acids.
12/23/2023 3

4.  Two molecules of acetyl CoA form acetoacetyl CoA, which
condenses with another molecule of acetyl CoA to form
Hydroxymethylglutaryl CoA (HMG-CoA).
 Reduction of HMG-CoA produces Mevalonate.
 This reaction, catalyzed by HMG-CoA reductase, is the major
rate limiting step of cholesterol synthesis.
12/23/2023 4

5.  The adrenal cortex and the gonads also synthesize cholesterol
in significant amounts and use it as a precursor for steroid
hormone synthesis.
 Cholesterol is packaged in chylomicrons in the intestine and
in very-low-density lipoprotein (VLDL) in the liver. It is
transported in the blood in these lipoprotein particles, which
also transport triacylglycerols.
 As the triacylglycerols of the blood lipoproteins are digested by
lipoprotein lipase, chylomicrons are converted to Chylomicron
remnants, and VLDL is converted to IDL and subsequently to
LDL.
12/23/2023 5

6. These products return to the liver, where they bind to receptors
in cell membranes and are taken up by endocytosis and
digested by Lysosomal enzymes.
LDL is also endocytosed by nonhepatic (peripheral) tissues.
Cholesterol and other products of lysosomal digestion are
released into the cellular pools.
The liver uses this recycled cholesterol, and the cholesterol that
is synthesized from acetyl CoA, to produce VLDL and to
synthesize bile salts.
12/23/2023 6

7. Structure of cholesterol
 Cholesterol has the basic steroid nucleus structure,
 Cholesterol is very hydrophobic.
 Cholesterol is the major sterol in animal tissues.
 A sterol is a steroid with 8 to 10 carbon atoms in the side chain at C-
17 and an alcohol hydroxyl group at C-3.
12/23/2023 7

8.  Cholesterol synthesis occurs in the cytoplasm with enzymes
in both the Cytosol and the endoplasmic reticulum.
 Regulatory mechanisms must exist to balance the rate of
cholesterol synthesis within the body against the rate of
cholesterol excretion.
Cholesterol Biosynthesis
12/23/2023 8

9.  An imbalance in this regulation can lead to an
elevation in circulating levels of plasma cholesterol,
causing the possibility of coronary artery disease,
 Whereas, excessive secretion of cholesterol into the
bile can result in precipitation of cholesterol in the
gall bladder and bile duct.
Cholesterol Biosynthesis
12/23/2023 9

10.  The first two reactions in cholesterol synthetic pathway are
similar to those in the pathway that produces ketone bodies;
they result in the production of HMG CoA
 First, catalyzes the Condensation of two acetyl
CoA.
 Next, catalyzes the addition of a Third
molecule of acetyl CoA .
12/23/2023 10

11. Cont…
1
3
2
12/23/2023 11

12.  Liver parenchymal cells contain two isoenzyme forms
of HMG CoA synthase. Such as
 The cytosolic participates in Cholesterol synthesis, and
 The mitochondrial functions for ketone bodies synthesis.
Cont….
12/23/2023 12

13.  The structure of cholesterol suggests that its synthesis
involves multimolecular interactions; yet all of the 27
carbons are derived from one precursor, acetyl CoA.
 Acetyl CoA can be obtained from several sources, such as:
β-oxidation of fatty acids,
oxidation of ketogenic amino acids:leucine and lysine,
pyruvate dehydrogenase reaction.
12/23/2023 13

14.  Carbons 1, 2, 5, 7, 9, 13, 15, 18, 19, 20, 22, 24, 26, and 27 of
cholesterol are derived from the methyl group of acetyl CoA
and the remaining 12 carbons of cholesterol from the
carboxylate atom of acetyl CoA.
 The synthesis of cholesterol requires significant reducing
power, in the form of NADPH.
 Provided by G6PD and 6-PGD of the HMP pathway
12/23/2023 14

15. • The committed step and major point of regulation of
cholesterol synthesis in stage 1 involves reduction of HMG-
CoA to mevalonate, a reaction catalyzed by
, an enzyme embedded in the membrane of the
endoplasmic reticulum.
12/23/2023 15

16. HMG-CoA reductase contains eight membrane-spanning
domains, and the amino terminal domain, which faces the
cytoplasm, contains the enzymatic activity.
The reducing equivalents for this reaction are donated by
two molecules of NADPH.
The regulation of the activity of HMG-CoA reductase is
controlled in multiple ways.
12/23/2023 16

17. Cont..
12/23/2023 17

18. #1. Feed- back inhibition
Cholesterol is a feed - back inhibitor of HMG CoA
reductase, thus decreasing further cholesterol
synthesis.
12/23/2023 18

19. #2. Hormonal regulation: (Through +po4 / -po4)
Glucagon favors of the inactive form of HMG CoA reductase
In contrast, insulin favors of the active ( dephosphorylated)
form of HMG CoA reductase.
12/23/2023 19

20. #3. Sterol- mediated regulation of transcription
The synthesis of cholesterol is also regulated by the amount of
cholesterol taken up by the cells during lipoprotein
metabolism.
CMR internalized by liver cells, and LDL internalized by the
cells of the liver and peripheral tissues, provide cholesterol,
which causes a decrease in transcription of the HMG CoA
reductase gene, leading to a decrease in de -novo cholesterol
synthesis .
12/23/2023 20

21. SRE = sterol regulatory element; SREBP = sterol regulatory element
binding protein; SCAP = SREBP cleavage-activating protein
Regulation of HMG CoA reductase.
12/23/2023 21

22. SREBP1-a specifically enhances transcription of genes required
for HMG-CoA reductase expression by binding to the sterol
regulatory element (SRE) upstream of the reductase gene.
When bound, the rate of transcription is increased. SREBPs,
after synthesis, are integral ER proteins, and the active component
of the protein is released by two proteases :- SCAP (SREBP
cleavage-activating protein) and S2P (site 2 protease).
12/23/2023 22

23. Once released, the active amino terminal component travels to the
nucleus to bind to SREs. The soluble SREBPs are rapidly turned over
and need to be continuously produced to effectively stimulate
reductase mRNA transcription.
When Cytoplasmic sterol levels rise, the sterols bind to SCAP and
inactivate it, thereby leading to a decrease in transcription of the
reductase gene, and less reductase protein being produced.
12/23/2023 23

24. Stage 2: Conversion of Mevalonate to Two Activated Isoprenes
Stage 3: Condensation of Six Activated 5-Carbon Isoprenes to
Form the 30-Carbon Squalene
Stage 4: Conversion of Squalene to the Four-Ring Steroid
Nucleus
12/23/2023 24

25. Biosynthesis Summary
12/23/2023 25

26. #4. Inhibition by drugs
Simvastatin, Lovastatin and mevastatin are reversible
competitive inhibitors of HMG CoA reductase.
They are used to decrease plasma cholesterol levels in patients
with hypercholesterolemia .
Structural similarity of HMG and simvastatin, a
clinically useful cholesterol-lowering drug of the
“statin” family.
12/23/2023 26

27. Substrate: acetyl-CoA
Product: cholesterol
Function: de novo synthesis of endogenous cholesterol
Subcelullar location: cytosol and endoplasmic reticulum
Organ location: liver, intestine, adrenal cortex, ovaries, testes and
placenta make the largest contributions to the body´s cholesterol
pool
12/23/2023 27