Lipids
Lipids are organic compounds formed mainly from alcohol and fatty
acids combined together by ester bond. Lipids are used in the body
as source of energy.
Other functions of different types of lipids will be discussed later in
details with every type.
Lipids = alcohol ( mainly glycerol) + fatty acids
Glycerol is polyhydric alcohol containing 3 hydroxy groups.
Fatty acids
General formula: R-COOH
Types:
saturated and unsaturated
1- Saturated fatty acids (with no double bonds)
The most important saturated fatty acids are:
Most commonly occurring saturated fatty acids are:
1- Butyric acid: CH3CH2CH2 COOH or C4:0
It is present mainly in butter,
C4:0 means it contains 4 carbon atoms and zero double bonds.
2- Valeric acid: CH3(CH2)3COOH or C5:0 (present in butter)
3- Caproic acid: CH3(CH2)4COOH or 6:0 it is present in butter and coconut
oil
4- Lauric acid: CH3(CH2)10COOH or C12: 0 (present in palm oil, laurels)
5- Myristic acid : CH3(CH2)12COOH or C14: 0 (present in palm oil)
6- Palmitic acid: CH3(CH2)14COOH or C16:0
7- Stearic acid: CH3(CH2)16COOH or C18:0
Palmitic and stearic acids are common in all animal and plant fats.
8- Lignoceric acid: CH3(CH2)22COOH or C24: 0
It is present in brain and myelin sheath of nerves. Also in peanut oil.
- Fats rich in saturated fatty acids (e.g butter) are solid in nature due to
high melting point of saturated fatty acids.
- Increased rate of saturation increase the risk of high cholesterol
level.
Numbering of carbon atoms:
a- counting from carbon of carboxylic acid group (-COOH) which
take no. 1, then the adjacent carbon is 2 and so on.
b- counting from carbon adjacent to carboxylic carbon i.e from
carbon 2 by this the numbering will be α, β, γ, δ and so on
NB: The last carbon (methyl carbon) is called omega carbon (ω).
Unsaturated fatty acids (contain one or more double bond):
a) Unsaturated FA containing one double bond
(monounsaturated):
1- Palmitoleic acid 16:1(9): 16 means 16 carbon atoms, 1 means
one double bond and 9 means this double bond is between carbons 9
and 10
CH3(CH2)510CH=9CH(CH2)7COOH It is present in all fats.
2- Oleic acid 18:1(9): present in all fats
CH3(CH2)710CH=9CH(CH2)7COOH
3- Nervonic acid 24: 1(15): It is present in brain
CH (CH )
16CH=15CH(CH
) COOH
b- Unsaturated FA containing more than one double bond
(polyunsaturated): They include:
- Linoleic acid 18:2(9,12): ω-6 fatty acid
CH3(CH2)4 13CH=12CH CH2 10CH=9CH(CH2)7COOH
- Linolenic acid 18:3(9,12,15): ω-3 fatty acid
CH3 CH2 16CH=15CH CH2 13CH=12CH CH2 10CH=9CH(CH2)7COOH
Linoleic and linolenic acids are essential Fatty acids: They are
needed for normal growth. They are not formed in the body and so must
be taken in diet so they are called essential fatty acids. They are
present in fish and vegetable oils e.g. corn oil , peanut, cottonseed,
soyabean and many plant oils.
- Arachidonic acid : 20: 4 (5,8,11,14): ω-6
CH3 (CH2)4 15CH=14CH CH2 12CH=11CH CH2 9CH=8CH CH26CH=5CH(CH2)3COOH
It is the precursor to prostaglandins, prostacyclins, and thromboxanes
-Eicosapentaenoic
(an
acid : 20: 5 (5,8,11,14,17): ω-3
omega-3 fatty acid because of double bond 3 C from distal end)
Draw the structure??
Polyunsaturated oils are liquid at room temperature and in the
refrigerator. Monounsaturated oils are liquid at room temperature but
start to solidify at refrigerator temperatures. See the table below for
sources.
Polyunsaturated fats help your body get rid of newly formed cholesterol.
Thus, they keep the blood cholesterol level down and reduce cholesterol
deposits in artery walls. Recent research has shown that
monounsaturated fats may also help reduce blood cholesterol as long as
the diet is very low in saturated fat.
Fats That Lower
Cholesterol
Polyunsaturated fats
Monounsaturated fats
Sources
Examples
certain plant oils safflower, sesame, soy, corn and
sunflower-seed oils, nuts and
seeds
certain plant oils
olive, canola and peanut oils,
avocados
Classification of lipids
I- Simple lipids:
Formed only from fatty acid and alcohol. The most common type is
neutral fat.
Neutral fats: the most important and most abundant group of fats in
nature. They may be fats or oils which have the same chemical
structure and same chemical properties, but differ in the state at room
temperature, fats are solid (rich in saturated fatty acid) and oils are
liquid (high amount of unsaturated fatty acid).
Chemical structure:
They are formed from glycerol and three molecules of fatty acids
combined together by ester bond. Since the three –OH groups of
glycerol are esterified, the neutral fat is also called: triglycerides
(TG) or triacylglycerol (TAG). The 3 fatty acids may be similar or
different.
The main site for storage of fat in human body is cells of
adipose tissue located in subcutaneous fat and around
important organs.
Dietary sources of TAG: Full cream milk products, butter,
cottonseed oil, sesame oil, linseed oil and olive oil. Also in
marine oils e.g. cod liver oil.
Functions of TAG:
1- source of energy. It is the main source of energy in case
of starvation
2- help to stabilize organs in their position such a kidney
Neutral fats (TAG or TG) metabolism
Digestion: TAG are so large to be absorbed (enter intestinal
mucosa then blood) so they must be degraded first. Enzyme that
degrade fats is called: lipase
In mouth: No or little digestion (lingual lipase).
In stomach: Little or no digestion in adults because:
1- No significant amount of gastric lipase
2- pH of stomach is about 1-2 which is not suitable for the lipase
action.
Gastric lipase can act in babies mainly , where the pH of stomach
is much higher than in adults (pH= 5) due to decrease in HCl.
Gastric lipase digest milk fat.
In intestine:
The major site of lipid digestion occurs in small intestine, mainly by
pancreatic lipase (steapsin).
Hormonal regulation of lipid digestion:
Passage of the acid gastric content (chyme) into the duodenum
stimulate the secretion of two GIT hormones: secretin and
cholecystokinin (CCK).
Secretin: stimulates liver and pancreas to secrete watery solution rich
in bicarbonate which make pH suitable for lipase action.
Cholecystochinin (CCK): Acts on cells of pancreas to release lipase.
Also causes contraction of gall bladder and discharge of bile into
duodenum..
Gasric lipase digest only
milk fat
Chyme
Secrets HCO3- watery solution and
Pancreatic lipase (steapsin), the main
enzyme in lipid digestion
Passage of chyme stimulate
secretion secretin and CCK
hormones from duodenum
Role of bile salts in lipid digestion: TAG are water insoluble making a
difficulty in their digestion by water soluble lipase in intestine. Bile salts
emulsify the fats increasing the surface area of interaction with lipase
and so increase the rate of digestion.
- Bile salt form a watery
sheath around hydrophobic
TAG molecules (form
micell) so increase the
attack of lipase with lipid
molecules
Action of steapsin:
remove fatty acids in positions 1, 3 in neutral fat, leaving 2- monoacyl
glycerol (2- monoglyceride) and two fatty acids. Steapsin not on C2.
G Fatty Acid1
l
y
c
e Fatty Acid2
r
o
l Fatty Acid3
Triglyceride
Lipase
2 H2 0
G
l
y
c Fatty Acid2
e
r
o
l
+
Fatty Acid1
Fatty Acid3
2 Free Fatty Acids
2-Monoglyceride
28% of 2- monoacyl glycerol are converted by isomerase into 1monoacyl glycerol which is then converted into glycerol and fatty acid
by steapsin.
So, the end products of digestion are: Glycerol, Fatty acids and
monoacylglycerol
Absorption:
Monoacylglycerols and free fatty acids (FFA), are now easy to be
absorbed by intestinal mucosa by the help of bile salt that convert them
into water soluble compounds (micelles).
In intestinal mucosa:
In the presence of TAG synthetase enzyme, long chain FAs (more than
12 C) combine again with glycerol to reform triacylglycerols (TAG).
The resynthesized TAG aggregates and coated with protein to form
lipoprotein called chylomicron. TAG carried on chylomicron pass
through lymphatics to blood and circulate in blood as lipoprotein.
TAG in blood:
In blood, an enzyme called: Lipoprotein lipase (clearing factor)
hydrolyses TAG carried on chylomicron into fatty acids and
glycerol.
Now: Free fatty acids produced from hydrolysis of TAG will enter
the tissues to be oxidized to produce energy or re-synsesized into
TAG and stored if no need of energy.
NB: short chain FAs (less than 12 C) enter blood directly and
carried by albumin to tissues (muscles or adipose tissues).
Chylomicron
Overview of lipid digestion and absorption
Two bags of fresh frozen plasma. The bag on
the left was obtained from a donor with
Hyperlipidemia, while the other bag was
obtained from a donor with normal serum
lipid levels
Question:
Complete:
Fat digestion requires…………. which is synthesized in
pancreas and …………….. synthesized in liver
Orlistat (marketed under the trade name Xenical by roche in most countries: It is
anti-obese drug, inhibits pancreatic lipase (steapsin). When lipase activity is
blocked, triglycerides from the diet are not digested (not hydrolysed into absorbable
free fatty acids), and are excreted undigested instead. Caloric intake is then reduced
and weight is decreased. At the recommended therapeutic dose of 120 mg three
times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Side effects include :
- steatorrhea (oily, fatty loose stools due to
unabsorbed fats reaching the large intestine)
- frequent or bowel movements.
- Affect absorption and uptake of lipid soluble
vitamins so it is recommended to take supplement of
vitamin A,D,E, K
-cases were reported for severe liver injury, kidney
stones and pancreatitis
How orlistat act??
NB:
TAG is not only taken with diet, but also synthesized in our body
by the liver.
The synthesis of TAG will be discussed later (Lecture 4).
Both dietary and synthesized TAG could be used directly as source
of energy or stored in adipose tissue and muscles for later use as
source of energy.
Fate of TAG in tissues:
1- Stored in the form of depot fat: Mainly under the skin, acting as
insulator against loss of heat. Neutral fats also stored in the
abdominal cavity which help in fixation of certain organs e.g. kidney.
2-
Excreted in milk of lactating women.
3-
Excreted in stool.
4- Used as reserve source of energy. Fatty acids are released and
oxidized for energy production.
Oxidation of fatty acids (present in TAG) serve as the major fuel
storage reserve in the body. In addition, fatty acid oxidation is the
major source of energy to the body during starvation.
Steps of TAG oxidation:
1- Release of fatty acids from TAG (lipolysis):
Fatty acids are the part to be oxidized so the first step is release of fatty
acids from TAG. This process is initiated by hormone- sensitive lipase
(HSL) which removes fatty acids from TAG. HSL is activated by anti-
insulin hormones (adrenaline, glucagon, GH, cortison) and inhibited by
insulin.
2-Activation of fatty acids:
Before its oxidation, fatty acid must be firstly activated to its active
form called: acyl CoA.
In the presence of ATP and CoA, the enzyme thiokinase (or called
Acyl CoA synthetase) catalyses the activation of long chain fatty acids
into acyl CoA.
RCOOH+2ATP + CoASH
→ RCO~SCoA
acyl CoA
3- Beta oxidation of fatty acids:
It is the major pathway of oxidation (catabolism or breakdown) of
saturated fatty acids in which two carbons are removed from activated
fatty acid, producing acetyl CoA, NADH and FADH2
Site: in the mitochondria of all tissues particularly in the liver. So there
is no fatty acid oxidation in RBCs which have no mitochondria.
NB: FA is not oxidized in brain
Note that: fatty acids with less than 12 carbons (short and medium
chain fatty acids) are activated in mitochondria then oxidized. While
activation of long chain fatty acids (more than 12 C) occurs in
cytoplasm (their thiokinase are cytoplasmic enzymes).
Transport of long chain fatty acyl CoA into mitochondria:
Carnitine shuttle
Long chain fatty acyl CoA cannot penetrate mitochondrial membrane (as
mitochondrial membrane is impermeable to CoA). They need a carrier to transport
them into mitochondria. This carrier is Carnitine which transports active fatty acid
by the help of 3 enzymes:
Carnitine acyltransferase I (CAT-1)
Carnitine - acylcarnitine translocase
Carnitine acyltransferase II (CAT-2)
Steps of transport: 1) acyl group is transferred from acylCoA into carnitine by CAT-1
to give acyl carnitine and free CoA which remains in cytoplasm.
2) Acyl carnitine is transported into mitochondria by the help of Carnitine acylcarnitine translocase.
3) CAT-2 catalyses the transfer of acyl group from acyl carnitine to CoA to give acyl
CoA and free carnitine which go back to cytoplasm by translocase enzyme.
Inhibitor of carnitine shuttle: malonyl CoA which inhibits carnitine acyltransferase I
Sources of carnitine: diet (meat products), synthesized from amino acids lysine and
methionine in liver and kidney.
Mitochondria
Steps of β- oxidation: See figure. Each cycle yield acyl CoA with
2 carbon atoms less, acetyl CoA, NADH and FADH2
Energy yield from β- oxidation:
Each β- oxidation cycle yields:
one NADH+H+ (which give 3 ATP via respiratory chain)
one FADH2
(which give 2 ATP via respiratory chain)
one acetyl CoA (oxidized through Kreb's cycle to yield 12 ATP).
Note:- - 2 ATP are utilized initially for fatty acid activation.
- The last cycle produce two acetyl CoA.
Question: Oxidation of one molecule of palmitic acid yields 129
ATP ( How?).
Energy yield from one molecule of palmitic acid
(16C): palmitic undergo 7 cycles of oxidation
With Production of 8 acetyl CoA
8 acetyl CoA x12 ATP = 96 ATP
7 NAH x3 = 21
7FADH2 x 2= 14
Total =131
2ATP utilized for FA activation
, so net is 129 ATP
C16
→ C14 + Acetyl CoA
Regulation of β- oxidation:
Oxidation of fatty acids is controlled by the rate of release of free fatty
acids from adipose tissues (lipolysis), which is inhibited by food
intake and insulin, and stimulated by starvation, adrenaline, glucagon,
thyroxin, glucocorticoids and growth hormone (the factors that
regulate the action of HSL).
Fate of Acetyl CoA:
1- Oxidation in kreb's cycle to CO2 + H2O and energy
2- Synthesis of:
a- fatty acids
b- ketone bodies
c- cholesterol
e- Acetyl choline
d- Adrenal cortical hormones
3- Detoxication by conjugation e.g. sulfonamides