The document discusses lipid metabolism, including β-oxidation of fatty acids, formation and utilization of ketone bodies, de novo synthesis of fatty acids, and disorders of lipid metabolism such as hypercholesterolemia, atherosclerosis, fatty liver and obesity. It provides details on the multi-step processes of β-oxidation of fatty acids, ketogenesis, fatty acid synthesis, and cholesterol conversion to bile acids and steroid hormones. Disorders are discussed in relation to abnormalities in lipid metabolism and risk factors.
2. CONTENTS
β-Oxidation of saturated fatty acid (Palmitic acid)
Formation and utilization of ketone bodies
Ketoacidosis
De novo synthesis of fatty acids (Palmitic acid)
Biological significance of cholesterol
Conversion of cholesterol into bile acids, steroid
hormone and vitamin D
Disorders of lipid metabolism: Hypercholesterolemia,
atherosclerosis, fatty liver and obesity.
3. β-oxidation of saturated fatty acids
The fatty acids in the body are mostly oxidized by
β-oxidation.
β-Oxidation is the oxidation of fatty acids on the β-
carbon atom.
This results in the sequential removal of a two
carbon fragment , acetyl CoA.
The β-oxidation of fatty acids involves three stages:
1. Activation of fatty acids occurring in the cytosol;
2. Transport of fatty acids into mitochondria;
3. β-Oxidation proper in the mitochondrial matrix.
4. Fatty acid activation:
Fatty acids are activated to acyl CoA by thiokinases or acyl
CoA synthetases.
The reaction occurs in 2 steps and requires ATP, coenzyme
A and Mg2+.
Fatty acid reacts with ATP to form acyladenylate which then
combines with coenzyme A to produce acyl CoA.
Transport of fatty acids into mitochondria:
Carnitine carrier system is used for the transport of
activated fatty acids from cytosol to mitochondria.
This occurs in 4 steps:
1. Acyl group of acyl CoA is transferred to carnitine catalysed
by carnitine acyl transferase I
2. The acyl-carnitine is transported across the membrane to
mitochondrial matrix by a specific carrier protein.
3. Carnitine acyl transferase ll converts acyl-carnitine to acyl
CoA.
4. The carnitine released returns to cytosol for reuse.
5. β-Oxidation proper: (4 reactions)
(1)Oxidation :
Acyl CoA undergoes dehydrogenation
by an FAD-dependent flavoenzyme,
acyl CoA dehydrogenase.
A double bond is formed between α and
β carbons.
(2)Hydration :
Enoyl CoA hydratase brings about the
hydration of the double bond to form β -
hydroxyacyl CoA.
(3)Oxidation :
β -Hydroxyacyl CoA dehydrogenase
catalyses the second oxidation and
generates NADH.
The product formed is β –ketoacyl CoA.
(4)Cleavage :
Liberation of a 2 carbon fragment, acetyl
CoA from acyl CoA.
This occurs by a thiolytic cleavage
catalysed by β-ketoacyl CoA thiolase
6.
7. Ketogenesis
The synthesis of ketone bodies occurs in the Iiver.
The enzymes for ketone body synthesis are located in
the mitochondrial matrix.
Acetyl CoA, pyruvate or some amino acids, is the
precursor for ketone bodies.
Reactions in Ketogenesis:
(1)Two moles of acetyl CoA condense to form
acetoacetyl CoA by the action of thiolase.
(2)Acetoacetyl CoA combines with another molecule of
acetyl CoA in the presence of HMG CoA synthase to
produce β –hydroxy β -methyl glutaryl CoA (HMG
CoA).
8. (3)HMG CoA lyase cleaves
HMG CoA to produce
acetoacetate and acetyl
CoA.
(4)Acetoacetate can undergo
spontaneous
decarboxylation to form
acetone.
(5)Acetoacetate can be
reduced by a
dehydrogenease to β-
hydroxybutyrate.
9. Utilization of ketone bodies
The ketone bodies (water-soluble) are easily
transported from the liver to various tissue.
The two ketone bodies- acetoacetate and β-hydroxy
butyrate are important sources of energy for skeletal
muscle, cardiac muscle/ renal cortex etc.
Tissues which lack mitochondria cannot utilize ketone
bodies.
The production and utilization of ketone bodies is more
significant when there is a short supply of glucose to
tissues, as in starvation, and diabetes mellitus.
During prolonged starvation, ketone bodies are the
major fuel source for the brain and other parts of CNS.
The ketone bodies can meet 50-70% of the brain's
10. Reactions of ketone
bodies:
β-Hydroxybrutyrate is
converted to
acetoacetate
Acetoacetate is
activated to aceto acetyl
CoA by the enzyme
thiophorase
Thiophorase is absent in
liver, hence ketone
bodies are not utilized
by the liver.
Thiolase cleaves aceto
acetyl CoA to 2 moles of
acetyl CoA
11. Ketoacidosis
Both acetoacetate and β-hydroxybutyrate are strong
acids.
Increase in their concentration in blood would cause
acidosis.
ketone bodies in the blood dissociate and release H+
ions which lower the pH.
Further, plasma volume in the body is reduced due to
dehydration caused by the excretion of glucose and
ketone bodies.
Diabetic ketoacidosis may result in coma, and even
death, if not treated.
Rapid treatment of diabetic ketoacidosis is required to
correct the metabolic abnormalities and the associated
water and electrolyte imbalance.
Insulin administration is necessary to stimulate uptake
of glucose by tissues and inhibition of ketogenesis
12. De novo synthesis of fatty
acids
De novo (new) synthesis of fatty acids occurs
predominantly in liver, kidney, adipose tissue and
lactating mammary glands.
The enzymes required are present in the
cytosomal fraction of the cell.
3 stages of fatty acid synthesis:
1. Production of acetyl CoA and NADPH
2. Conversion of acetyl CoA to malonyl CoA
3. Reactions of fatty acid synthase complex.
13. Production of acetyl CoA and NADPH:
Fatty acid synthesis requires Acetyl CoA and
NADPH.
Acetyl CoA is produced in the mitochondria by the
oxidation of pyruvate and fatty acids, degradation of
carbon skeleton of certain amino acids, and from
ketone bodies.
As acetyl CoA is not permeable to mitochondria, it is
converted to citrate.
Citrate is freely transported to cytosol where it is
cleaved by citrate lyase to liberate acetyl CoA and
oxaloacetate.
Oxaloacetate in the cytosol is converted to malate.
Malic enzyme converts malate to pyruvate.
NADPH and CO2 are generated in this reaction,
which are utilized for fatty acid synthesis
14. Formation of malonyl CoA:
Acetyl CoA is carboxylated to malonyl CoA by the
enzyme acetyl CoA carboxylase.
Reactions of fatty acid synthase complex:
The remaining reactions of fatty acid synthesis are
catalysed by a fatty acid synthase (FAS) complex.
The 2 carbon fragment of acetyl CoA is transferred to
ACP(acyl carrier protein) of fatty acid synthase. The
acetyl unit is then transferred from ACP to cysteine
residue of the enzyme. Thus ACP site falls vacant.
The enzyme malonyl CoA-ACP transacylase transfers
malonate from malonyl CoA to bind to ACP.
The acetyl unit attached to cysteine is transferred to
malonyl group.The malonyl moiety loses CO2 which
was added by acetyl CoA carboxylase. This reaction is
catalyzed by β-ketoacyl ACP synthase
15. β -Ketoacyl ACP reductase reduces ketoacyl group to
hydroxyacyl group.
β –Hydroxyacyl ACP undergoes dehydration. A
molecule of water is eliminated and a double bond is
introduced between α and β carbons.
A second NADPH-dependent reduction, catalysed by
enoyl-ACP reductase, occurs to produce acyl-ACP.
The carbon chain attached to ACP is transferred to
cysteine residue.
The enzyme palmitoyl thioesterase separates
palmitate from fatty acid synthase.
16.
17. Biological significance of
cholesterol
Cholesterol is found exclusively in animals, hence it is
often called as animal sterol.
Cholesterol is amphipathic in nature(possess both
hydrophilic and hydrophobic regions).
It is a structural component of cell membrane.
Cholesterol is the precursor for the synthesis of all
other steroids in the body(steroid hormones, Vit D &
bile acids)
It is an essential ingredient in the structure of
lipoproteins in which form the lipids in the body are
transported.
Fatty acids are transported to liver as cholesteryl
esters for oxidation.
18. Degradation of Cholesterol
The steroid nucleus (ring structure) of cholesterol
cannot be degraded to CO2 and H2O.
Cholesterol (50%) is converted to bile acids (excreted
in feces), serves as a precursor for the synthesis of
steroid hormones, vitamin D, coprostanol and
cholestanol.
Synthesis of Vitamin D:
7-Dehydrocholesterol,an intermediate in the
synthesis of cholesterol, is converted to
cholecalciferol(vitamin D3) by ultraviolet rays in the
19. Synthesis of Bile acids:
The bile acids possess 24
carbon atoms, 2 or 3
hydroxyl groups in the
steroid nucleus and aside
chain ending in carboxyl
group.
Bile acids are amphipathic in
nature.
They serve as emulsifying
agents in the intestine &
participate in the digestion
and absorption of lipids.
Bile acid synthesis takes
place in the liver.
In the bile, the conjugated
bile acids exist as sodium
and potassium salts which
are known as bile salts
20. Synthesis of steroid hormones
from cholesterol:
Cholesterol is the precursor
for the synthesis of all the five
classes of steroid hormones
1. Glucocorticoids (eg:
cortisol)
2. Mineralocorticoids(eg:
aldosterone)
3. Progestins (eg:
progesterone)
4. Androgens (eg:
testosterone)
5. Estrogens(eg: estradiol).
21. Hypercholesterolemia
Increase in plasma cholesterol (> 200 mg/dl)
concentration is known as hypercholesterolemia.
It is observed in many disorders like Diabetes mellitus,
Hypothyroidism, Obstructive jaundice, Nephrotic
syndrome.
Control of hypercholesterolemia:
(1)Consumption of poly unsaturated fatty acids (PUFA)
(2)Dietary cholesterol : avoid cholesterol rich foods.
(3)Plant sterols : Certain plant sterols and their esters
reduce plasma cholesterol levels. They inhibit the
intestinal absorption of dietary cholesterol.
(4)Dietary fiber : Fiber present in vegetables decreases
the cholesterol absorption from the intestine
22. (5)Avoiding high carbohydrate diet
(6)lmpact of lifestyles :
Elevation in plasma cholesterol is observed in people
with smoking, abdominal obesity, Iack of exercise,
stress, high blood pressure, consumption of soft water
etc.
Therefore, adequate changes in the lifestyles will
bring down plasma cholesterol.
(7)Moderate alcohol consumption
(8)Use of drugs:
Drugs such as lovastatin which inhibit HMG CoA
reductase and decrease cholesterol synthesis.
Certain drugs-cholestyramine and colestipol-bind with
bile acids and decrease their intestinal reabsorption.
Clofibrate increases the activity of lipoprotein lipase
and reduces the plasma cholesterol and
triacylglycerols.
23. Atherosclerosis
Disease characterized by thickening or hardening of
arteries due to the accumulation of lipids, collagen,
fibrous tissue, calcium deposits etc. in the inner arterial
wall.
Atherosclerosis is a progressive disorder that narrows
and ultimately blocks the arteries.
The development of atherosclerosis and the risk for the
coronary heart disease (CHD) is directly correlated with
plasma cholesterol and LDL.
Certain diseases like diabetes mellitus,
hyperlipoproteinemias, nephrotic syndrome,
hypothyroidism etc. are associated with atherosclerosis.
24. Many other factors like obesity, high consumption of
saturated fat, excessive smoking, lack of physical
exercise hypertension, stress etc., are the probable
causes of atherosclerosis.
The increased levels of plasma HDL (good
cholesterol) are correlated with a low incidence of
cardiovascular disorder.
Strenuous physical exercise, moderate alcohol intake,
consumption of unsaturated fatty acids (vegetable
and fish oils), reduction in body weight-all tend to
increase HDL levels and reduce the risk of
cardiovascular disease.
Antioxidants (vitamins E and C or β-carotene) reduces
the risk of atherosclerosis , and thereby CHD.
25. Fatty liver
Fatty liver: Excessive accumulation of Triacylglycerols in
liver.
In the normal liver, Kupffer cells contain lipids in the form
of droplets.
In fatty liver, droplets of triacylglycerols are found in the
entire cytoplasm of hepatic cells.
This causes impairment in metabolic functions of liver.
Fatty liver is associated with fibrotic changes and
cirrhosis
Fatty liver may occur due to two main causes.
1. Increased synthesis of triacylglycerols
2. Impairment in lipoprotein synthesis.
26. Diabetes mellitus, starvation, alcoholism and high fat
diet are associated with increased mobilization of fatty
acids that often cause fatty liver.
Fatty caused by impaired lipoprotein synthesis may be
due to
1. a defect in phospholipid synthesis;
2. a block in apoprotein formation
3. a failure in the formation/secretion of lipoprotein.
Certain chemicals (e.g. ethionine, carbon tetrachloride,
lead, chloroform , phosphorus etc.) that inhibit protein
synthesis cause fatty liver.
Deficiency of vitamin E is associated with fatty liver.
Selenium acts as a protective agent in such a condition.
Endocrine factors : Certain hormones like ACTH,
insulin, thyroid hormones, adrenocorticoids promote
deposition of fat in liver .
27. Obesity
Obesity is an abnormal increase in the body weight
due to excessive fat deposition.
Overeating-coupled with lack of physical exercise-
contribute to obesity.
Clinical obesity is represented by body mass index
(BMI).
BMI (kg/ m2) = Weight (kg)
Height (m2)
Obesity is categorized into three grades:
1. Grade I obesity or overweight - BMI 25-30 kg/ m2 .
2. Grade ll or clinical obesity - BMI > 30 kg/ m2
3. Grade lll or morbid obesity - BMI > 40 kg/m2
28. Obesity is associated with many health complications
e.g. type ll diabetes, CHD, hypertension, stroke,
arthritis, gall bladder diseases.
obesity has genetic basis. Thus, a child born to two
obese people has about 75% chances of being obese
Leptin is regarded as a body weight regulatory
hormone. (This signals to restrict the feeding behavior
and limit fat deposition)
Any genetic defect in leptin or its receptor will lead to
extreme overeating and massive obesity.
White adipose tissue : The fat is mostly stored and
this tissue is metabolically less active.
Brown adipose tissue : The stored fat is relatively less
but the tissue is metabolically very active.
Brown adipose tissue is almost absent in obese
persons