For Medicals, paramedical, and allied health sciences students

1. Metabolism
of
Cholesterol

2. Cholesterol
 Structural component of every cell (in cell membrane)
 It provides a protective barrier
 To establish proper membrane permeability,
 Membrane fluidity &
 Nerve conduction
 Major components of lipoproteins
Metabolical role
 It involves
 Vit-D formation
 Synthesis of bile acids & Bile salts
 Steroid hormones
Polar
head
non polar
General formula-C27H45OH
Cyclo pentano perhydro-phenanthrene

3. In total cholesterol :
About 30% free form (un esterified) &
70% - cholesteryl esters form

4. Biosynthesis of Cholesterol
Sites Enzymes
location
Requirements Stages
All nucleated
cells including
arterial wall.
Major sites are
liver, intestine
Adrenal cortex,
testes & ovaries
Partly
endoplasmic
reticulum &
partly in
cytoplasm.
18moles of Acetyl -
CoA provides all
carbon atoms
36 moles of ATP
16 moles of
NADPH are required
1. Synthesis of HMG -CoA
2. Formation of Mevalonate
3. Production of Isoprenoid
units
4. Synthesis of squalene
5. Conversion of squalene to
cholesterol

5. Cytoplasmic
Stage-1: Synthesis of HMG -CoA

6. Endoplasmic reticulum
Stage-2: Formation of Mevalonate
CoA-SH

7. Stage-3: Production of Isoprenoid units
Mevalonate (6C)
Isopentenyl Pyrophosphate (IPP) (5C)
3ATP
3ADP+ Pi+CO2
3 Phosphorylation reaction &
one Decarboxylation reactions
Dimethylallyl pyrophosphate (5C)
Isomerase

8. Dimethylallyl pyrophosphate (5C)
IPP (5C)
IPP (5C)
FPP, NADPH +H+
NADP +PPi
Squalene Synthase
(Mg, Mn)
Stage-4: Synthesis of squalene
Transferase
PPi
Transferase
Geranyl pyrophosphate (10C)
Fernesyl pyrophosphate (15C)
Squalene
PPi
Currently
bisphosphonates
are used for
treatments of
osteoporosis as
inhibit FPP
synthesis & inhibit
osteoclast activity
preventing
demineralization
in osteoporosis

9. Step 5: Conversion of Squalene to Cholesterol
O
H +
CH3
H3C
CH3
HO
CH3
CH3
CH3
HO
CH3
Squalene
Squalene
monooxygenase
2,3-Oxidosqualene
cyclase
Lanosterol (30C)
20 Steps
Cholesterol
NADPH, O2
Squalene-
2,3-epoxide
•Shortening of the C-chain from 30 to 27
•Removal of the extra methyl groups at C4
•Migration of the double bond from C8 to C5
•Reduction of one double bond b/w C24 & C25

10. REGULATION

11. Hormonal regulation (Covalent modification)
Thyroid hormones
Phosphorylated form is inactive
Dephosphorylated form is active

12. Regulation of cholesterol biosynthesis by HMG-CoA
reductase
Durgs, eg. Compactin, statins (Mevastatin,
Lovastatin, Provastatin, Simvastatin)-
competitive inhibitors
Bile acids
High caloric diet

13. Transcriptional regulation of gene for HMG-CoA reductase
SCAP
(Intracellular
cholesterol
sensor)
Specific recognition
sequence

14. Formation of Cholesterol Esters
In plasma (HDL)
From the peripheral tissues to liver
In cells of liver, intestine & adrenal
cortex
C2 of lecithin
containing
PUFA
Endoplasmic reticulum

15. Wolman’s disorder
(Rare genetic disorder)
accumulation of
CE & TGs in
the cells
Cause bloating or abdominal
distention, vomiting & significant
hepatosplenomegaly

16. Excretion :
• Unabsorbed portion of the cholesterol (50%) by intestinal bacteria form cholestanol
& coprostanol excreted fecal
• Remaining cholesterol (50%) is converted to bile acids ,which are excreted in the bile
as bile salts

17. Synthesis of Bile acids in the liver
Metabolic Fate of
Cholesterol
Synthesis of Steroid hormones
Required for synthesis of Vit- D
Excreted in feces as cholestanol &
coprostanol (fecal sterols)
Metabolic Fate of Cholesterol

18. Formation of Bile Acids
Vit-C

19. Conjugation in bile
Conjugation more with glycine
than taurine
Na+ & K+
Formation of Bile salts
Sodium & potassium
glycocholate or
taurochenodeoxycholate
99% bile acids in duodenum are
reabsorbed.
1% excreted in stools after
modification as 2o bile acids
In colon
Intestinal bacteria

20. Functions of Bile acids:
• Act as efficient emulsifying agents
• Facilitate the enzymatic digestion & absorption of dietary lipids & fat soluble
vitamins (forming mixed micelle )
• Conversion of cholesterol into bile acids in the liver - prevents the body from
becoming overloaded with cholesterol
• Act as regulatory molecules: activate nuclear receptors, G-protein coupled
receptors TGR5, cell signaling pathways in the liver
• Bile acids activating signaling pathways are novel drug targets to treat of obesity, Type-2
DM, Hyperlipidemia & atherosclerosis

21. Cholelithiasis (Cholesterol gall stone disease)
• Due to increased syn of cholesterol & decreased syn
of bile acids
• Bile is supersaturated with cholesterol results crystals
that nucleated into solid crystals – forms stones (gall
stones)
– Mucin secreted by gallbladder, promotes the
process of nucleation
– apoproteins A-I & A-II inhibits, thus prevents the
gall stone formation

22. Cholecystitis
• Multiple stones may cause inflammatory changes
in the gall bladder
Treatment:
• Chenodeoxy cholic acid is used as a drug to
dissolve gall stones.
• Surgery is required when stones obstructed the
bile duct or for removing an inflamed gallbladder

23. Metabolism of Vitamin-D

24. Formation of Vitamin-D

25. Biochemical functions of Vitamin –D
• Calcitriol regulates serum calcium and phosphorus.
• Regulates the differentiation & proliferation of various cells
• Involved in the modulation of the immune system
Action on the Intestine Action on the bone Action on renal tubules
- Due to ↑se availability
of calbindin, the
absorption of Ca2+ is ↑sed
↑ses intestinal absorption
of Ca2+ & P from intestine
Calcitriol stimulates
osteoblasts → secrete ALP
→ ↑sed conc. of phosphate.
- Ionic products of Ca2+ &
P ↑ses leads to
mineralization
Increases reabsorption
& decreases excretion of
Ca2+ & P by renal
tubules

26. Cholesterol is the major precursor of the 5 classes of steroid
hormones
Mineralocorticoids (eg. Aldosterone)
Estrogens (eg: estradiol)
Progestin (eg: progesterone )
Androgens (eg: Testosterone)
Glucocorticoids (eg. cortisol)
SYNTHESIS OF STEROID HORMONES

27. Glucocorticoids
(eg. cortisol)
Mineralocorticoids
(eg. Aldosterone)
Cholesterol is the major precursor for steroid hormones

28. Hormone Site RH Functions
Glucocorticoids
(Cortisol /
corticosterone) -
produced in adrenal
cortex
Zona
fasciculate
cells
Adreno
corticotropic
hormone
(ACTH)
-Helps to promotes gluconeogenesis,
-favors lipolysis & protein break down.
- Protects against stress,
-Helps to maintain BP
Mineralocorticoids
(Aldosterone) –
produced in adrenal
cortex
Zona
glomurulos
a
cells
ACTH - Helps to regulates body’s water &
electrolyte balance
- Maintains blood volume & BP by
increasing Na+ reabsorption in exchange
for K+ & H+
Androgens
(testosterone) –
primarily in the
gonads (testicles ,
ovaries) & also in the
adrenal glands
Zona
reticularis
cells
ACTH Controls the development of male 2o sexual
characteristics
-Regulates sperm production
-Promotes increased muscle mass through
increased protein formation,
-Prevents bone resorption

29. Hormone Site RH Functions
Estrogen
(produced in
ovaries )
Follicle
stimulating
hormone
(FSH)
Controls the development of female 2o
sexual characteristics ,
Regulates menstrual cycle,
Contributes to the hormonal regulation
of pregnancy & lactation,
Prevents bone resorption
Progesterone
by the ovaries,
placenta & adrenal
glands
Luteinized
granulosa
cells
LH its role in thickening the lining of the
uterus each month.
Prepares uterus lining for implantation
of ovum

30. Disorders of Cholesterol

31. • Normal levels of cholesterol in serum is150 to 200mg/dl
HYPERCHOLESTEROLEMIA:
High conc. of cholesterol in the blood.
It is a combination of "hyperlipidemia" (elevated levels of lipids in
the blood) & "hyperlipoproteinemia" (elevated levels of lipoproteins
in the blood).

32. High conc. of cholesterol in serum
Physiological causes Pathological causes
Unhealthy Diet: increased
intake of Saturated FA or
consumption of rich
carbohydrates.
High consumption alcohol &
smoking
Lack of physical exercise
Type -II Diabetes Mellitus,
Obstructive jaundice (due to blockage of
excretion)
Hypothyroidism (receptors on liver is
reduced due to decreased thyroid hormones)
Nephrotic syndrome

33. Atherosclerosis
Thickening or hardening &
narrowing of coronary arteries due to
the accumulation of lipids
(cholesterol) in the inner arterial walls
& producing blockages in the vessels
that carry blood to the heart.

34. • Oxidants like superoxide radicals, nitric oxide,
H2O2 causes oxidation of LDL
• Oxidized LDL is taken up by macrophages of the
immune system
• Macrophages engorged with oxidized LDL to form
Foam cells.
• Foam cells are trapped in the walls of the blood
vessels, lead to the formation of plaques and
narrowing of the arteries
• Plaques (foam cells) are composed of smooth
muscles cells, connective tissues & lipids that
accumulate in the intima of the arterial wall.
Formation of Plaque and arterial narrowing

35. • Foam cells accumulate causing a fatty steak to
develop in the blood vessels
• Damaged endothelial cells cannot produce
Prostaglandins I2, Prostacyclin & platelets to
aggregate, releases Thromboxane-A (favors
thrombus formation & increased BP)
• Releases Platelet Derived Growth Factor (PDGE)
contributes to plaque formation and narrowing of
the arteries

36. Parameter Effect
Sex Male are more affected
Female incidence is more after menopause
Genetic factor Derangement of lipoprotein metabolism leads to high lipid levels and familial
hypercholesterolemia
Hyperlipidemia Increased levels of serum cholesterol, triglycerides, LDL, Lp-a
Low levels of HDL is associated with atherosclerosis
Hypertension Mechanical injury to the vessel wall due to raised blood pressure
Cigarette
smoking
Reduced levels of HDL and accumulation of carbon monoxide
Diabetes
Mellitus
Risk due to coexistence of other risk factors like obesity, hypertension and
hyperlipidemia
Other risk
factors
Raised LDL and decreased HDL, lack of exercise& more stress,
high caloric intake, diet containing large quantities of saturated fats,
use of oral contraceptive, alcoholism and diabetes mellitus,
Factors Responsible For Atherosclerosis

37. Myocardial Infarction
Myocardial ischemia / MI results from reduction of coronary blood
flow to an extent that leads to insufficiency of oxygen supply to the
myocardial tissue

38. Chronically elevated serum cholesterol (LDL-C)
formation of atheromatous plaques in the arteries
(atherosclerosis)
lead to progressive stenosis (narrowing) or even complete
occlusion (blockage) of the involved arteries.
leads to obstruct blood flow (low oxygen supply) in
coronary artery
results in a myocardial infarction or heart attack.

39. Prevention :
– Avoid smoking : Nicotine increases lipolysis →acetyl CoA → cholesterol
– Physical exercise: Lowers LDL-C & raises HDL-C, reduces TG levels
– Consumption of PUFA : Required for the esterification of cholesterol & ω-
3 FAs reduce LDL-C
– Take more dietary fibers: Increase the reabsorption of bile salts & ↓se the
absorption of dietary cholesterol)
– Consume sufficient natural antioxidants: Prevent the formation of
oxidized LDL
 Restricting consumption of alcohol
 Drug therapy

40. Hypolipidemic drugs
Action
Statins
(lovastatin, simvastatin,
atorvastatin, prevastatin,
pitavastatin, fluvastatin,
rosuvastatin)
- Inhibits HMC-CoA reductase
- Improving the endothelial functions
- Modulating inflammatory response
- Maintaining plaque stability
- Preventing blood clot formation
Fibrates (Clofibrate) Increasing beta oxidation of fatty acids
Aspirin Prevents thrombus formation (antiplatelet activity)
Bile acid binding resins
(Cholestyramine)
-Cholestyramine & Cholestipol
-Decreases the reabsorption of bile salts
Nicotinic acid -Inhibits lipolysis

41. Hypocholesterolemia
• Decreased cholesterol levels in plasma
Causes:
– Hyper thyroidism
– liver necrosis
– Malabsorption syndrome
– Pernicious anemia
– Haemolytic jaundice
– Inherited hypolipoproteinaemias

42. LIPID PROFILE SPECIAL INVESTIGATION
Ref. ranges
Triglycerides 100-150 mg/dl Cardiac Enzymes CK-MB & LDH4
Total cholesterol 150- 200 mg/dl Cardiac proteins Myoglobin & Troponin- I
LDL cholesterol 60- 140 mg/dl Other investigations Homocysteine &
Lipoprotein (a)
HDL cholesterol 30- 60 mg/dl
VLDL < 35mg/dl
Diagnostic Investigations
(Biochemical Markers)

43. OBESITY
Anyone who is more than
20% above the standard
weight for the same age, sex,
and race, is considered to be
overweight.

44. Causes
Genetic influences
Physiological -Overeating than caloric requirement,
-Pregnancy
-Use of oral contraceptives for
prolonged period
- Post menopausal women
Metabolic Diabetes mellitus, Hyperlipidemia
Hormonal Hypothyroidism,
Hypogonadism
Hypopituitarism,
Cushing’s syndrome

45. Metabolic changes in Obesity
– Serum triglyceride levels are raised due to hyperinsulinism
– Serum Cholesterol levels are raised
– Mobilization of Free Fatty Acid is reduced
– Lipoprotein lipase activity brings delipidation of TG, circulating chylomicrons &VLDL
– Increased activity of the enzyme would lead to increased FFA accumulation in adipose
tissue and leads to fat deposition
– Promotes lipogenesis and inhibits lipolysis

46. Believe your self
Have a nice day to all