It is about lipid metabolism for pharmacy students

1. 1

2. • Biological lipids are a chemically diverse group of organic substances in plant
and animal tissues
– Common & defining feature of which is their insolubility in water
– Lipids are hydrophobic compounds, soluble in organic solvents
– Most membrane lipids are amphipathic;
– having a non-polar end and a polar end
– lipids found either as:
» Compartmentalized (in membrane)
» Droplets (in adipocytes)
» Lipoprotein particles
2

3. Lipids con’t…
 Unlike the polysaccharides ,proteins and nucleic acids, lipids are
not polymers
 Lipids may be polar or nonpolar (amphipathic).
 Major polar lipids include fatty acids, cholesterol,
glycerophosphatides, and glycosphingolipids.
 Very short chain fatty acids and ketone bodies are readily soluble in water
 Nonpolar lipids serve principally as storage and transport forms
of lipid
e.g. Triacylglycerols (also triglycerides) and cholesteryl esters.
3

4. 4

5. 5

6. Functions of lipids…
• Some lipids serve as precursors for the synthesis of
complex molecules
– For example, acetyl-CoA is used for the synthesis of cholesterol.
• Lipoproteins: which are complexes of lipids and proteins
are involved in the transport of lipids in the blood and
components of cell membrane.
• Some lipids serve as hormones, Vit- D
• Eicosanoids which have profound biological actions are
derived from the essential fatty acids
6

7. Classification of Lipids
1. Simple lipids: esters of fatty acids with
different alcohols
(a) Neutral fats (Triacylglycerol, TG):
These are triesters of fatty acids with glycerol
 Fats & Oils (TAG)
Most fatty acids in humans exist as triacylglycerols,
in which all three hydroxyl groups on glycerol are
esterified with a fatty acid
– The difference between fat and oil is only physical one
– Thus, oil is a liquid while fat is a solid at room
temperature
7

8. Classification of Lipids
b. Other Simple Lipids
• Waxes:- Esters of fatty acids with alcohols (C16H33OH) or
other higher straight chain alcohols
• Cholesterol esters :are esters of fatty acid with cholesterol
• Vit A (Retinol) and Vit D are esters of palmitic or stearic acids
respectively
2. Complex (or compound) lipids; These are esters of fatty acids
with alcohols containing additional groups such as phosphate,
nitrogenous base, carbohydrate … etc
• Phospholipids, Glycolipids, Sphingophospholipids
Lipoproteins & Others

9. 3. Derived lipids; These are the derivatives obtained on
the hydrolysis of simple and complex lipids which
possess the characteristics of lipids include
• These include glycerol and other alcohols , fatty acids,
mono- and diacylglycerols, steroid hormones,
cholesterol and ketone bodies.
9

10. Simple lipids
Storage Lipids
• Fats & Oils (TAG)
• used almost universally as stored forms of energy in living
organisms
– Fatty acids:
• Hydrocarbon derivatives  are aliphatic carboxylic acids
» Found in nature as esterified forms
» Exists in body free or as fattyacyl esters
» Most contain an even number of carbon atoms
• Fatty acids fill two major roles in the body:
» as the components of membrane lipids
» as the major components of stored fat in form of TAG

11. Non-polar  polar
11
Fatty acids with less than 12 and more than 24 carbon atoms are uncommon
in biological systems.
Palmitic acid (l6C) and stearic acid(18) are the most common.
Most of the fatty acids have even number of carbon atoms.

12. Fatty acids occur
• More than 90% of the fatty acids found in plasma are in the
form of fatty acid esters (primarily triacylglycerol,
cholesteryl esters, and phospholipids)packed in circulating
lipoprotein particles
 Unesterified (free) fatty acids are transported in the
circulation in association with albumin
 Lipids sources:
 Animal fat, egg yolk, butter and cheese are lipids of animal
origin
 vegetable or cooking oils are lipids of plant origin
12

13. • PROPERTIES OF TRIACYLGLYCEROLS
• A few important properties of triacylglycerols, which have biochemical
relevance, are discussed below
• 1. Hydrolysis :Triacylglycerols undergo stepwise enzymatic hydrolysis to finally
liberate free fatty acids and glycerol. The process ofhydrolysis, catalysed by
lipasesis important for digestion of fat in the gastrointestinal tract and fat
mobilization from the adipose tissues.
• 2. Saponification :The hydrolysis of triacylglycerols by alkali to produce glycerol
and soaps is known as saponification.
• Triacylglycerol + 3 NaOH = Glycerol + 3 R-COONa (soaps)
• 3. Rancidity :Rancidity is the term used to represent the deterioration of fats
and oils resulting in an unpleasant taste. Fats containing unsaturated fatty acids
are more susceptible to rancidity. Rancidity occurs when fats and oils are
exposed to air, moisture, light, bacteria etc.
• Hydrolytic rancidityoccurs due to partial hydrolysis of triacylglycerols by
bacterial enzymes. Oxidative rancidity is due to oxidation of unsaturated fatty
acids. This results in the formation of unpleasant products such as dicarboxylic
acids, aldehydes, ketones etc. Rancid fats and oils are unsuitable for human
consumption
13

14. 14
Short chain=4-6 Medium chain=8-12 Long chain= >12
Very long chain >24

15. 15
This is due to biosynthesis of fatty acids mainly occurs
with the sequential addition of 2 carbon units.

16. 16

17. 17

18. 18

19. 19

20. 20

21. 21

22. Fatty acids con’t...
• The C= C double bonds are found in the fatty acids
– plant & fish fats
– vegetable oils & are liquid at room temperature
• the kinks made by double bonded carbons , prevent the
molecules from packing tightly together
• the side chain is unsaturated (one or more double bonds are present)
• All naturally occurring unsaturated fatty acids are cis-isomers
• Cis and trans isomers are not interchangeable in cells
• Only cis isomers can fit into cell membrane because of bend at
double bond
22

23. Fig-FA1 Saturated fatty acids and unsaturated fatty acids.
Cis and trans
double bonds in fatty
acid side chains.
•Note that the cis
double bond causes
the chain to bend.
23

24. Trans Fats (Hydrogenation)
- Hydrogen adds to the double bonds of vegetable oil (using
transition metal catalyst such as Ni)
• - Liquid oils are converted to semi-solid fats
• Melting point is increased
 Trans fatty acids are present in certain foods,
 Arising as a by-product of the SFA during hydrogenation or
‘hardening’ of natural oils during the manufacturer
margarine and they seriously affects health
 margarine is the conversion of oil to fat by adding H2 , in
the presence of Ni catalyst

25. Trans Fats
• “Partially hydrogenated” oils may
contain higher levels of trans fats
• Trans fats are more solid than oils
• Trans fats increase the shelf life of
foods
25

26. Fat & Health
(omega-3 fatty acids from fish) lower the risk of heart disease by
decreasing the level of cholesterol in the blood.
However,
if the double bond of the unsaturated triacylglycerol is trans, the
beneficial effect is lost.
• Trans fats,primarily synthesized instead of naturally occurring,
act like saturated fats
• Unlike other fats, trans fats both raise your "bad" (LDL)
cholesterol and lower your "good" (HDL) cholesterol levels in
the blood.
26

27.  Saturated fats tightly packed, clog arteries as atherosclerosis
 because of double bonds, polyunsaturated fats do not pack well
like building a wall with bricks vs. irregular-shaped objects
27
plant fats are much higher
in PUFA’s than animal fats

28. • Increase in the number cis-double bonds leads to produces more
fatty acid to bend or ‘kinks ‘
• This has profound significance on molecular packing in
membrane
NB: In general, addition of double bonds decreases the melting
temperature (Tm) of a fatty acid, whereas increasing the chain
length increases the Tm.
Because membrane lipids typically contain LCFA, the presence of
double bonds in some fatty acids helps
 maintain the fluid nature of those lipids
28
Saturation of un Saturated fatty acids

29. Fat & Health
• Fats are used to build cell membranes, insulate the body, and
store energy for later use.
• It is recommended that no more than 20-35% of a person’s
caloric intake should come from lipids.
• A high intake of saturated triacylglycerols is linked to heart
disease
• Saturated fats stimulate cholesterol synthesis in the liver, which
can lead to cholesterol plaques building up inside arteries.
• The result is high blood pressure, heart attack, and even stroke.
• Unlike other vegetable oils, oils from palm and coconut trees are
very high in saturated fats
29

30. Desaturation of Fatty Acids
 Mammalian hepatocytes can readily introduce double
bonds at the Δ9 position of fatty acids but cannot
introduce additional double bonds between C-10 and the
Ѡ-methyl-terminal end .
 Plants are able to introduce double bonds into fatty acids
in the region between C10 and the Ѡ -end and
 therefore can synthesize Ѡ3 and Ѡ 6 polyunsaturated fatty acids
30
Figure . Microsomal Δ9 desaturase Oxygen and either NADH or NADPH are necessary for
the reaction. The enzymes appear to be similar to a monooxygenase system involving
cytochrome b5

31. 31

32. 32

33. 33

34. 34

35. 35

36. 36

37. 37

38. Essential fatty acids
• They are not synthesized in the body ,are dietary essentials
in humans
• They must be supplement in diets
 linoleic acid- which is the precursor of arachidonic acid, the
substrate for prostaglandin synthesis
 α-linolenic acid- important for growth and development
 Arachidonic acid- becomes essential if linoleic acid is deficient
in the diet
NB: Humans lack the desaturases, the enzymes to insert
double bonds at carbon atoms beyond C-9 in the fatty acid
chain.
• This is the basis for the nutritional essentiality of the
polyunsaturated linoleic and α-linolenic acids
38

39. Essential fatty acids con’t...
• Linoleic acid is called an omega-6 acid,
39
Linolenic acid is called an omega-3 acid,
n: indicate the position of the first double bond

40. Good sources of ‘omega-6 fatty acids
40
Most vegetable oil: Sunflower oil, Corn oil, Soybean oil
• Cotton seeds oil
• Nuts and cereals
• Poultry, eggs
• Avocado

41. Good sources of ‘omega-3 fatty acids’
• Oily fish (salmon, mackerel, sardines, tuna)
• Pumpkin seeds, sesame seeds
• soybean oil

42. 42

43. Human deficiency of EFA
Essential fatty acid (PUFA) deficiency can result
 visual and neurologic abnormalities
 Degenerative changes in arterial wall
 Enhance fatty liver and cholesterol levels
 Infants & babies with low fat diet develop typical skin lesions
but improved with EFA (linoleic acid)
43

44. Eicosanoid
• Arachidonic acid is the most common
precursor of eicosanoids
• Arachidonic acid is polyunsaturated
fatty acid with 20 carbons and 4 double
bonds (20:4 Δ5,8,11,14)
• Eicosanoids are derived from
arachidonic acid,
• They are a family of very potent biological
signaling molecules that act as short-range
messengers
• mainly act as “local” hormones
(paracrine hormone), affecting the cells
that produce them or neighboring cells.
• carry messages to the nearby cells

45. • Because arachidonic acid cannot be synthesized denovo in the
body, the diet must contain either, arachidonic acid or other
precursor from which arachidonic acid can be produced
eg. linoleate which is essential fatty acid, which is present in
plant oils
45

46. 46
Fig 2 . Release of arachidonic acid from membrane lipids. The binding of a stimulus to its
receptor activates pathway
• In response to, activation plasma membrane receptor by a
variety of stimuli like Histamine and the cytokines
• phospholipase A2 attacks membrane phospholipids, and
releasing arachidonate from the middle carbon of glycerol
Eicosanoid Hormones con’t….

47. Eicosanoid Hormones con’t…
• Arachidonate is the major precursor of several classes of
signal molecules:
• Arachidonic acid is enzymatically metabolized by three
major pathways
• The two pathways that have been most well studied are the
– cyclooxygenase pathway (which produces prostaglandins and
thromboxanes) and
– the lipoxygenase pathway (which produces leukotrienes).
• The eicosanoids, which include the prostaglandins (PG),
thromboxanes (TX), and leukotrienes (LT), are among the
most potent regulators of cellular function in nature and are
produced by almost every cell in the body.
47

48. “Eicosanoid”(eicosa-, Greek for
"twenty") is the collective term
for oxygenated derivatives of
20-carbon essential fatty acids:
The cytochrome P450 pathway
generates eicosanoids with less
- physiologic function

49. 49
Some Functions of Thromboxane A2 vs pI2
Leukotrienes have muscle
contractant and chemotactic
properties and are important
in allergic reactions and
inflammation

50. Some physiological functions of PG ,TX2 and LT
• Our knowledge of the of biologic actions of the
endogenous eicosanoids is incomplete, several actions are
well-established to allow their application in a variety of
clinical situations or diseases.
• For example, drugs that are analogs of PGE1 and PGE2
suppress gastric ulceration,
• in part by inhibiting secretion of hydrochloric acid in the
mucosal cells of the stomach.
• Analogs of PGE1 are used in the treatment of sexual impotence.
• The stimulatory action of PGE2 and PGF2 on uterine muscle
contraction , induce labor and to control postpartum bleeding.
50

51. physiological functions of PG ,TX2 and LT…
• Eicosanoids participate in many processes in the body,
particularly
– the inflammatory response that occurs after infection or injury
• The inflammatory response is the mechanism by w/c the body’s
make efforts to
– destroy invading organisms and to repair damage
Eg . control of bleeding through the formation of blood clots
• During the process of protecting the body , the inflammatory
response can produce
 symptoms such as pain, swelling, and fever
51

52. physiological functions of PG ,TX2 and LT…
 Eicosanoids also regulate smooth muscle contraction
 eg . particularly in the intestine and uterus.
• They increase water and sodium excretion by the kidney and
are involved in regulating blood pressure
• For example, some eicosanoids serve as constrictors and
others as dilators of blood vessels , eg .TXA2 and PGI2
• They are also involved in regulating bronco constriction and
bronchodilation ( eg. Leukotrine)
52

53. • PGH2 may be converted to the thromboxane TXA2, a
reaction catalyzed by TXA2 synthase
enzyme is present in high concentration in platelets.
• The predominant eicosanoid in platelets is TXA2,
• a potent vasoconstrictor and a stimulator of platelet
aggregation (initiates thrombus formation) at sites of
vascular injury
• as well as thrombus formation in the vicinity of a
ruptured atherosclerotic plaque in the lumen of vessels
– such as the coronary arteries
53

54.  PGE2、= Decrease blood pressure；
 PGE2, PGF2 promotes ovulation, it stimulate& uterinemuscle
contraction delivery to induce labor
 TX：TXA2 promotes coagulation and thrombosis
 PGI2：inhibiting coagulation and thrombosis
 LT：regulate bronchial smooth muscle cells
 TXA2 and PGI2 have important antagonistic biologic effects on;
Vasomotor , smooth muscle and platelet aggregation
54

55. 1. Classification of Storage lipids
 The fats and oils used almost universally as stored forms of
energy in living organisms w/c are derivatives of fatty
acids
 Two types of fatty acid triacylglycerols and waxes
 They are esters of fatty acids with alcohols.
Eg. Fats and waxes
Most naturally occurring TAGs are mixed; they contain 2 or more
different FAs
•The polar hydroxyls of glycerol & the polar carboxylates of the FAs
are bound in ester linkages
55

56. Fig-F Glycerol &
TAG
The mixed TAG
shown here has 3
different FAs
attached to the
glycerol backbone.
56
Exogenesis source: Dietary
• Endogenous : synthesis in Liver and tissue storage
• The exogeneous: Triglycerides transported by Chylomicrons and
endogenous (VLDL)
• Are energy source when plasma glucose is decreased
• Orlistat, an ant obesity drug, inhibits gastric and pancreatic lipases function ,
there by decreasing fat absorption, resulting in loss of weight

57. 57
Water Repellents
Melting points (60 to 100 oC) are generally higher
than those of TAGs
Biological waxes find a variety of applications in the:
Pharmaceutical, cosmetic, and other industries

58. 58

59. 59

60. 60

61. 61

62. 62

63. 63
Plasmalogens

64. phospholipids
Phosphotidylcholines(lecithins)
 the most abundant of phospholipids of cell membrane
 represent a large proportion of body’s store of choline
 Choline is important in nerve transmission and store of labile
methyl group
 Dipalmitoyl choline (lecithin )is a very effective surface active agent
and lowers surface tension in alveoli lungs
 Lecithin along with sphongomylin maintains the shape of alveoli
and prevent their collapse
 due to high surface tension of the surrounding medium
64

65. Snake venoms
• Hydrolysis of one of the ester bonds in a phospholipid
produces lysolecithin which is hemolytic , i.e, causes hemolysis
of RBCs
• The venoms of a number of snakes , scorpion, poisonous
spiders and stinging insects contain phospholipases (lecithinase
or cephalinase which act on lecithin /cephalin to release
lysolecithin/ lysocephalin.
65

66. Sphingolipids of two type
66
Sphingo
-

67. 67

68. Sphingolipids….
• Glycolipids are lipids that contain carbohydrate residues
in addition to the alcohol (sphingosine) and a very long
chain fatty acid (24-carbon series).
• They are present in cerebral tissues and, therefore, are
called cerebrosides.
– They are also referred to as sphingogalactolipids.
• Sphingomyelins are found in large amounts in brain and
nerves and
• in smaller amounts ; in lung, spleen, kidney, liver and blood
• Sphingomyelins differ from lecithins in that they contain
sphingosine as the alcohol instead of glycerol
68

69. Glycophospholipids cont.
• Sphingomyelin has a phosphocholine or phospho-
ethanolamine head group
• Sphingomyelins are common constituent of plasma
membranes in brain and nerves
• Cerebrosides:
•have a single sugar linked to ceramide
–those with galactose are characteristically found in
–the plasma membranes of cells in neural tissue
–those with glucose found in
–the plasma membranes of cells in non neural tissues
69

70. Niemann-Pick disease
• It is a rare hereditary fatal disease that occurs in infants
• It is due to abnormal accumulation of sphingomyelins in the
liver , spleen and brain tissues caused by
– hereditary deficiency of a lysosomal enzyme, sphingomyelinase
• The enzyme is involved in regular turnover of the
sphingomyelins; therefore, in its absence,
– the sphingomyelins cannot be metabolized and get accumulated
• Clinically, the patients present with enlargement of
abdomen, liver and spleen
• The children show progressive mental retardation and
majority of them die within two years
70

71. Gaucher’s disease
• This is a rare inherited lipid storage disease due to the
abnormal metabolism of cerebrosides
• It is characterized by the deficiency of the enzyme
glucocerebrosidase.
• The enzyme removes the glucose residue from the
cerebrosides molecules during the metabolism of
gangliosides
71

72. 72

73. Steroids
 Steroids are complex molecules containing four fused
rings.
• The four fused rings makeup
‘cyclopentanoperhydrophenanthrene’(CPPP) or
‘sterane’ ring
• Sterane ring is also called as steroid nucleus. The most abundant
steroids are sterols which are steroid alcohols.
73
Fig. structure of
steroid nucleus

74. Cholesterol
• Is the most abundant steroid in the body.
• Exogenous cholesterol comes from diet
• Endogenous cholesterol is synthesized by
the liver
• 70 % of cholesterol associated with
cellular components
• 30 % is in the plasma (⅓ free form ,⅔
esterfied )
• Insoluble in water (need a water soluble
carrier).
• Transported by HDL and LDL
Has methyl CH3- groups, alkyl chain, and
-OH attached to the steroid nucleus

75. Cholesterol…
• Cholesterol, exclusively found in animals, is the most abundant
animal sterol.
• Is obtained from meats, milk, and eggs.
• Is synthesized in the liver from fats, carbohydrates and proteins.
Clogs arteries when high levels& form plaque (because it is
insoluble in blood), contribute to cardiovascular disease
75
Gallstones form in gallbladder

76. Steroids are Derived From Cholesterol
76
Estrogen
Testosterone

77. Cholesterol…
• Cholesterol is the precursor of all five classes of steroid
hormones:
– glucocorticoids,
– mineralcorticoids,
– androgens,
– estrogens and progestins.
These hormones are synthesized in the adrenal cortex, ovaries,
testes, and ovarian corpus luteum.
77

78. Cholesterol is the ‘Mother-Steroid
One molecule with many functions
• It is also the most abundant sterol , contain alcohol at c-3
• Steroids with diverse physiological functions are derived or
synthesized in the body from cholesterol
Thus are ;
a) Vitamin D, 7-dehydrocholesterol derived from cholesterol is
provitamin of vitamin D.
b) Bile acids , They are required for the formation of bile salts.
c) Hormones of adrenal cortex, are cortisol , corticosterone and
aldosterone ,are derived form cholesterol
d) Female sex hormones, they are progesterone and estrogen
e) Male sex hormones they are testosterone and aldrosterone
78

79. 79

80. 80
PUFAs that serve to increase the fluidity of membranes as compared to saturated fatty
acid. Cholesterol and its esters are important components of cell

81. Nb .Read on Sphingolipids at Cell Surfaces Are Sites of
Biological Recognition
81

82. 82