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 acidsGeneral 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)5

10CH=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

CH3(CH2)716CH=15CH(CH2)13COOH

b- Unsaturated FA containing more than one double bond (polyunsaturated) Or 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. - 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

-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 acid : 20: 5 (5,8,11,14,17): ω-3

(an 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 Sources Examples

Polyunsaturated fats certain plant oils safflower, sesame, soy, corn and sunflower-seed oils, nuts and

seeds

Monounsaturated fats certain plant oils olive, canola and peanut oils, avocados

Classification of lipidsI- 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: 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 stabelize 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

Passage of chyme stimulate secretion secretin and CCK hormones from duodenum

Secrets HCO3- watery solution andPancreatic lipase (steapsin), the main enzyme in lipid digestion

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.

28% of 2- monoacyl glycerol are converted by isomerase into 1- monoacyl glycerol which is then converted into glycerol and fatty acid by steapsin.

Glycerol

Fatty Acid1

Fatty Acid2

Fatty Acid3

Lipase

Glycerol

Fatty Acid3

Fatty Acid1Fatty

Acid2

Triglyceride

2-Monoglyceride

+

2 Free Fatty Acids

2 H20

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).

Overview of lipid digestion and absorption

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 threetimes 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.

How orlistat act??

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.

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 shuttleLong 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 ISources of carnitine: diet (meat products), synthesized from amino acids lysine and methionine in liver and kidney.

 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 CoA8 acetyl CoA x12 ATP = 96 ATP7 NAH x3 = 217FADH2 x 2= 14Total =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