Cholesterol is the major sterol in the animal tissues.
Cholesterol is present in tissues and in plasma either as free cholesterol or as a storage form, combined with a long-chain fatty acid as cholesteryl ester. This presentation provide an overview of how cholesterol and ketone bodies are synthesised.
3. Objectives
▪ Definition cholesterol and ketones
▪ Describe cholesterol synthesis pathways
▪ Describe ketogenesis
▪ Regulations of cholesterol biosynthesis
4. Definition
▪ Cholesterol is a waxy, fat-like substance found in all cells
of the human body
▪ Cholesterol is essential for cellular structure and function
▪ It plays a crucial role as a component of cell membrane
and as a precursor of steroid hormones
▪ It is synthesised in the cell cytosol and endoplasmic
reticulum from acetyl-CoA.
5. Cholesterol biosynthesis
▪ Three molecules of acetyl –CoA are converted to the 6 –
carbon mevalonic acid.
▪ The first two steps are condensation reaction leading to the
formation of 3 –hydroxyl 3 –Methylglutaryl CoA (HMG –CoA)
▪ These reactions occur in cytoplasm and are catalyzed by
AcetoAcetyl –CoA thiolase (Thiolase) and HMG –CoA
synthase.
7. Conti…
▪ MHG –CoA is then catalyzed by HMG reductase which is a
rate limiting enzyme
▪ This leads to the irreversible formation of mevalonic acid
which is later converted to isopentyl pyrophosphate then to
squalene.
▪ HMGR is embedded in endoplasmic reticulum.
▪ Hormones like insulin and tri –iodothyronine increases its
activities
8. Conti…
▪ While glucagon and cortisol inhibit it.
▪ Mevalonate is phosphorylated in two reaction requiring
kinases and ATP to be converted to isoprene pyrophosphate
then further to isoprene units
▪ Isoprene units goes through 21 steps to be converted to
squalene by a hormone called squalene synthase.
▪ Squalene is later converted to 7 –dehydrocholesterol which
is finally converted to cholesterol
10. ketones
▪ Ketones are organic compounds that the body produces
when it breaks downs fat for energy in the absence of
sufficient carbohydrates
▪ They can serve as alternative source of energy for the brain
and muscles when glucose levels are low, such as during
fasting, starvation, Atkins die (low- carb diet), or certain
medical conditions like diabetes.
11. Ketogenesis
❑It is the formation of ketone bodies in the liver
mitochondria
❑Ketone bodies includes:
▪ Acetoacetate acid (CH3-CO-CH2-COOH)
▪ β -Hydroxybutyric acid (CH3-CHOH-COOH
▪ Acetone (CH3-CO-CH3)
12. Conti…
▪ Ketone bodies are formed from Acetyl CoA resulting from β
oxidation of fatty acids in excess of optimal function of
kreb’s cycle.
▪ Under the normal fed state, the hepatic production of
acetoacetate and β hydroxybutyrate in minimal and the
concentration of these compounds in the blood is very low
(doe not exceed 1mg).
13. Conti…
▪ Most acetyl CoA fatty acid or pyruvate oxidation enter the
citric cycle only if fat and carbohydrates degradation are
balanced.
14. Steps of synthesis of ketone bodies
1. Two molecules of acetyl CoA react with each other in the
presence of thiolase enzyme to form acetoacetyl CoA.
2. Condensation of acetoacetyl CoA with acetyl CoA to form 3
hydroxyl 3 methyl glutaryl CoA (HMG CoA) catalyzed by
HMG CoA synthase
3. HMG CoA lyase enzyme catalyzes the cleavages of HMG
CoA to acetoacetate and acetyl CoA
15. Conti…
4. Acetoacetate produces β –hydroxybutyrate in a reaction
catalyzed by β –hydroxybutyrate dehydrogenase (β –OH
butyrate –DH) in the present NADH.
5. Both acetoacetate and β –hydroxybutyrate can be
transported across the mitochondrial membrane and the
plasma membrane of the liver cells, enters the blood
stream to be used as fuel by other cells of the body.
16. Conti…
6. In the blood stream, small amounts of acetoacetate are
spontaneously (non –enzymatically) decarboxylated to
acetone.
7. Acetone is volatile and can not be detected in the blood
system
8. The odor of acetone may be detected in the breath and
also in urine of a person who has high level of ketone
bodies in the blood.
e.g. in severe diabetic ketoacidosis while under normal
conditions, acetone formation is negligible.
17. Gluco
se
Pyruvate Acetyl-CoA
Acetyl-CoA + Acetyl-CoA
Acetoacetyl-CoA
Thiolase
CoA SH
HMG-CoA
HMG synthase
CoA SH
Flow diagram Fatty Acids
NADH
FADH2
ETC ATP
β-oxidation