1. Dr. Ifat Ara Begum
Assistant Professor
Dept of Biochemistry
Dhaka Medical College, Dhaka
2. 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.
In plasma, both forms are transported in
lipoproteins
3. Plasma low-density lipoprotein (LDL) is
the vehicle of uptake of cholesterol and
cholesteryl ester into many tissues.
Free cholesterol is removed from tissues
by plasma high-density lipoprotein
(HDL) and transported to the liver,
where it is eliminated from the body
either unchanged or after conversion to
bile acids in the process known as
reverse cholesterol transport
4. The structure of cholesterol consists of
four fused rings (The rings in steroids are
denoted by the letters A, B, C, and D.),
with the carbons numbered in the
sequence, and an eight numbered, and
branched hydrocarbon chain attached to
the D ring.
5.
6.
7.
8. Cholesterol contains two angular methyl
groups: the C-19 methyl group is
attached to C-10, and the C-18 methyl
group is attached to C-13.
The C-18 and C-19 methyl groups of
cholesterol lie above the plane
containing the four rings.
9. Steroids with 8 to 10 carbon atoms in the
side chain and an alcohol hydroxyl group
at C-3 are classified as sterols. Much of
the plasma cholesterol is in the esterified
form (with a fatty acid attached at carbon
3), which makes the structure even more
hydrophobic .
10.
11. Cholesterol is the most abundant sterol in
humans and performs a number of
essential functions. For example-
It is a major constituent of the plasma
membrane and of plasma lipoproteins.
It is a precursor of bile salts/bile acid
It is a precursor of steroid hormones that
include adrenocortical hormones, sex
hormones, placental hormones etc
12. Also a precursor of vitamin D, cardiac
glycosides, Sitosterol of the plant
kingdom, and some alkaloids.
It is required for the nerve transmission.
Cholesterol is widely distributed in all
cells of the body but particularly
abundant in nervous tissue.
13. Cholesterol is derived from
Diet
De novo synthesis and
From the hydrolysis of cholesteryl esters
14. A little more than half the cholesterol of the
body arises by synthesis (about 700 mg/d), and
the remainder is provided by the average diet.
The liver and intestine account for
approximately 10% each of total synthesis in
humans.
Virtually all tissues containing nucleated cells
are capable of cholesterol synthesis, which
occurs in the endoplasmic reticulum and the
cytosol.
18. Regulation of cholesterol synthesis is exerted near
the beginning of the pathway, at the HMG-CoA
reductase step.
Competitive inhibition (by Statins)
Feed back inhibition (by cholesterol itself)
Covalent modification (Role of hormones)
Others:
Nutritional state: Fasting decreases but well fed
condition increases the enzyme activity.
Dietary intake of cholesterol decreases the
enzyme activity & endogenous synthesis And
vice versa
19. Competitive inhibition:
Statins (Lovastatin, Mevastatin,
Atorvastatin etc.) are the reversible
competitive inhibitors of HMG Co A
reductase.
They are used to decrease plasma
cholesterol levels in patients of
hypercholesterolemia.
20. Feed back inhibition
HMG Co A reductase is inhibited by
Mevalonate and Cholesterol.
Mevalonate is the immediate product of
HMG Co A reductase catalyzed reaction
whereas Cholesterol is the ultimate
product of the reaction pathway.
21. Covalent modification (Role of hormones)
Phosphorylation decreases the activity of the
reductase.
Glucagon favors formation of the inactive
(phosphorylated form) form, hence decreases the rate
of cholesterol synthesis. Glucocorticoids inhibits
the enzyme, too.
In contrast , insulin favors formation of the active
(dephosphorylated)form of HMG Co A reductase
and results in an increase in the rate of cholesterol
synthesis. Thyroid hormones stimulate the enzyme,
too.
Cholesterol synthesis ceases when ATP level is low
22. Inhibitors for HMG CoA reductase, thus
for the endogenous synthesis of
cholesterol:
Hypocholesterolemic drug
Fasting
Glucagon , Glucocorticoids
Increased dietary cholesterol
23. Stimulators for the HMG CoA
reductase, thus for the endogenous
synthesis of cholesterol:
Well fed state
Insulin, Thyroxine
Reduced dietary cholesterol
24. Synthesis of biological membrane/ steroid
hormone/7-dehydro cholesterol &
cholecalciferol (vitamin D)
Conversion to bile acids
Conversion to neutral sterols (e.g.
coprosterol) by intestinal bacterial flora)
25. The normal serum cholesterol concentration
ranges between 150- 220 mg/dl
Hypercholesterolemia (High serum cholesterol
concentration) is found in :
Diabetes mellitus
Nephrotic syndrome
Obstructive jaundice
Familial hypercholesterolemia
Billiary cirrhosis
Hypothyroidism
26. Hypocholesterolemia (Low serum
cholesterol concentration) is observed in:
Hyperthyroidism
Malnutrition
Malabsorption
Anemia
Physiologically lower levels are found in
children
Persons on cholesterol lowering drugs