Lipid Metabolism

 Introduction 

A) Properties:

1) Relatively insoluble in water,

2) Soluble in non-polar solvents, such as ether, chloroform, and benzene.

3) Lipids are organic compounds of biological nature that includes fats, oils and waxes.

4) Utilizable by living organisms.

Weight and distribution in the body:

==> In the normal mammal at least 10 to 20 percent of the body weight is lipid.

==> They form important dietary constituent on account of their high calorific value and fat soluble vitamins (vitamins A, D, E and K) along with the essential fatty acids

==> Distributed in all organs, particularly in adipose tissues in which lipids represent more than 90 percent of the cytoplasm of a cell.

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B) Digestion

(1) The digestion of fats starts in the small intestine where fats are emulsified (i.e. make  emulsion) by the bile salts and hydrolyzed by the pancreatic lipases to form free fatty acids.

(2) These free fatty acids combine with glycerol (produced by the glycolysis) to form triglycerides.

(3) Then triglycerides combine with proteins to form lipoproteins and enter into circulation to perform various biological functions such as oxidation, storage and formation of new lipids.

Thus the various fatty acids may exist in the free form as well as in the esterified form (Triglyceride) in blood.

Fatty acids are the immediate source for oxidation of fats in various tissues such as liver, adipose tissue, muscles, heart, kidney, brain, lungs and testes.

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C) Biological functions of Lipids

Lipids are stored in a relatively water – free state in the tissues in contrast to carbohydrates which are heavily hydrated to perform a wide variety of functions

1) Body lipids are reservoir of potential chemical energy and can be stored in the body in almost unlimited amount in contrast to carbohydrates. Furthermore, lipids have a high calorific value (9.3 calories per gram) which is twice as great as carbohydrate.

2) Responsible for membrane integrity and regulation of membrane permeability because lipids form the major constituent of biomembranes.

3) The subcutaneous lipids serve as insulating materials against atmospheric heat and cold and protect internal organs.

4) They serve as a source of fat soluble vitamins (Vitamin A, D, E and K) and essential fatty acids. (Linoleic, Linolenic and Arachidonic acid).

5) Lipids serve as metabolic regulators of steroid hormones and prostaglandins.

6) Lipids present in inner mitochondrial membrane actively participate in electron transport chain

7) Polyunsaturated fatty acids help in lowering blood cholesterol.

8) Squalamine, a steroid, is a potential antibiotic and antifungal agent.

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D) Phospholipids as the major component of biological membranes

1) Some lipids such as fatty acids, some phospholipids, have two groups: non-polar groups (hydrocarbon) and polar groups.

2) Those molecules are orientated at oil-water interfaces with the polar group in the water phase and the non-polar group in the oil phase.

3) A bilayer of such polar lipids has been regarded as a basic structure in biologic membranes.

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 Lipogenesis and Lipolysis 

A) Lipogensis:

It is the process in which lipid is formed form the union of glycerol and fatty acids obtained from the diet or by conversion of glucose into fat since acetyl CoA is the starting molecule for the synthesis of fatty acids.

B) Lipolyssis:

It is the breakdown of stored fates into free glycerol and fatty acids where:

==> Glycerol enters glycolysis and form acetyl coA which enters Kerbs cycle and produce energy

==> Fatty acids is converted to acetyl coA which enters Kerbs cycle and produce energy

Kerbs cycle starts with the combination with acetyl coA and Oxaloacetic acid, therefore oxaloacetate is necessary for the complete oxidation of fat and without it, acetyl CoA is converted into ketones (ketogenesis)

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 Fatty acids 

A) Properties of Fatty acids

1) The fatty acids are the basic units of lipid molecules.

2) Fatty acids are derivatives of aliphatic hydrocarbon chain that contains a carboxylic acid group.

3) They differ among themselves in hydrocarbon chain length, number and position of double bonds as well as in the nature of substituents.

4) Depending on the absence, or presence of double bonds, they are classified into saturated and unsaturated fatty acids.

5) Saturated fatty acids, do not contain double bonds.

6) The hydrocarbon chain may contain 12 to 18 carbon atoms. eg. palmi

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B) Essential fatty acids

Definition:

They are polyunsaturated fatty acids (FFA) that are not synthesized in the  body and required in the diet e.g Linoleic acid and Linolenic acid.

Function:

1. They are required for membrane structure and function.

2. Transport of cholesterol.

3. Formation of lipoproteins.

4. Prevention of fatty liver .

Deficiency:

- The deficiency of essential fatty acid results in phrynoderma or toad skin.

Phrynoderma: a rough dry skin eruption marked by keratosis and usually associated with vitamin (A) deficiency — called also toad skin

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C) Metabolism of fatty acids:

Biosynthesis of fatty acids

1. Occurs in all organisms and in mammals it occurs mainly in adipose tissue, mammary glands, and liver.

2. Fatty acid synthesis takes place in the cytosol in two steps.

a) Formation of medium chain fatty acid of chain length 16 carbon atoms.

b) Lengthening of this carbon chain in microsomes for larger fatty acids.

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The beta-oxidation of FA involves the following steps:

1. Fatty Acid Activation by Esterification with CoASH.

2. Membrane Transport of Fatty Acyl CoA Esters.

3. Carbon Backbone Reaction Sequence:

a) Dehydrogenation

b) Hydration

c) Dehydrogenation

d) Carbon-Carbon Cleavage (Thiolase Reaction).

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1. Fatty Acid Activation by Esterification with CoASH.

1) Fatty acids are relatively inert chemical molecules because they are hydrocarbon and hence they must be converted to an active intermediate for the initiation of beta-oxidation.

2) The activation of fatty acids takes place in the cytosol in the presence of ATP, coenzyme A and acyl CoA synthetase.

3) The activated fatty acid then enters into mitochondria with the help of a carrier protein called carnitine in the presence of a enzyme carnitine acyl transferase.

Net reaction:

FA + CoA + ATP ====> fatty-acyl-CoA + AMP + 2Pi + 34 kJ/mol

2.Membrane Transport of Fatty Acyl CoA Esters (carnitine shuttle)(the rate determining step).

===> Fatty-acyl-CoA can’t across the mitochondrial membrane to complete oxidation inside the mitochondria.

===> Thus carnitine which is a carrier protein in the mtochonderial membrane is used to transport Fattyacyl-CoA where Fatty-acyl-CoA is converted into Fatty-acyl-carnitine by the enzyme carnitine acyltransferase then a translocator within the mitochondrial membrane transport it to the matrix.

===> Into the matrix, acyle-carnitine is converted back to acyl-CoA.

===> Fatty acid  =< 12 carbons ===> enters the mitochondrial membrane without the need for carnitine huttle

===> Fatty acid =>14 carbons ===> must use carnitine shuttle.

===> It is the rate determining step

Clinical Consequences:

Deficiencies of carnitine or carnitine transferase activity are related to disease state.

1) Symptons include muscle cramping during exercise, severe weakness and death. Affects muscles, kidney, and heart tissues.

2) Muscle weakness related to importance of fatty acids as long term energy source.

3) People with this disease should take supplement diet with medium chain fatty acids that do not require carnitine shuttle to enter mitochondria.

3. Carbon Backbone Reaction Sequence:

1) Fatty acids are oxidised to CO2 and water with the liberation of large amount of energy.

2) Oxidation is brought about in the mitochondria because all the enzymes required for oxidation are present in the mitochondria.

3) Oxidation of fatty acids is of three types, based on the position of the carbon atom which gets oxidised (α, β and γ).

R—CH2—CH2—CH2—COOH

                                                                                                       γ           β          α

However β-oxidation of fatty acids is predominant (i.e. breack 2 carbon atoms) and widely prevalent and it provides large amount of energy than (α) and (γ) oxidation.

2 carbon atoms are broken through one cycle:

1st step is dehydrogenation

2nd step is hydration

3rd step is dehydrogenation

4th step break at beta-carbon

Energy obtained form one cycle:

1 FADH2 = 2ATP through the Electron Transport Chain

1 NADH = 3 ATP through the Electron Transport Chain

The energy obtained form the acetyl-CoA it is preferred to be calculated when we know the number of carbon atoms of the acetyl-CoA

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How to calculate energy obtained from fatty acid:

The amount of energy is according to the number of the carbon atom in the fatty acid molecules

For example:

==> Suppose we have a molecule of Palmitic acid which consists of 16 carbon atom

==> Note that 16 carbon atom (palmitic acid) is linked together by 14 bond (16-2) and we know that through the Beta-oxidaon each 2 carbons are broken per each cycle and thus we can calculate the number of cycles needed to break all the molecules

The number of cycles = no. of bonds / 2 = 14 /2 = 7

===> And we know from the previous pathway that each cycle produce one NADH and One FADH2

===> But for calculation of the number of acetyl-CoA molecule:

The number of Acetyl-CoA = number of cycle + 1 = 7 + 1 =8 mlecules

Thus:

Each acetyl-COSCoA through the TCA cycle produce = 3 NADH + FADH2 + 1 ATP

- Through the electron transport chain equals

3 NADH = 3 x 3ATP = 9 ATP

FADH2 = 1 x 2 ATP = 2ATP

Thus:

The total energy of one acetyl –CoA = 9 + 2 + 1 = 12 ATP

||||THUS the total energy:||||

8 acetyl-CoA produce = 12 x 8 = 96 ATP

7 NADH = 7 x 3 ATP = 21 ATP

7FADH2 = 7 x 2 ATP = 14 ATP

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 131 ATP

But we will subtract 2 ATP which are consumed through the converon of palmic acid into palmotyl-CoA

Thus the total energy obtained form Palmic acid = 131 -2 = 129 ATP

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