Lipid Metabolism Course outlines:  Fatty acid structure  Triglyceride structure  Metabolism of lipids in fed state  Digestion and absorption of dietary triacylglycerol  Fatty acid synthesis in liver from glucose  Synthesis of triacylglycerol in liver  Synthesis of triacylglycerol in adipose tissue  Choleserol metabolism  Lipoprotein metabolism  Metabolism of lipids in the fasting state  Fuel stores  Mobilization of adipose triacylglycerol  Fatty acid oxidation  Ketone body synthesis and utilization  Phospholipid metabolism

Definition of 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.

Tructure of fatty acids General formula: R-COOH Types: Saturated and unsaturated I- Saturated fatty acids (with no double bonds) The most important saturated fatty acids are: 1- Butyric acid: CH 3 CH 2 CH 2 COOH or C4:0: It is present mainly in butter, C4:0 means it contains 4 carbon atoms and zero double bonds. 2- Capric acid: CH 3 (CH 2 ) 8 COOH or C10: 0 3- Lauric acid: CH 3 (CH 2 ) 10 COOH or C12: 0 (present in palm oil, laurels) 4- Myristic acid : CH 3 (CH 2 ) 12 COOH or C14: 0 (present in palm oil)

Most commonly occurring saturated fatty acids are: 4- Palmitic acid: CH 3 (CH 2 ) 14 COOH or C16:0 5- Stearic acid: CH 3 (CH 2 ) 16 COOH or C18:0 Palmitic and stearic acids are common in all animal and plant fats. 8- Lignoceric acid: CH 3 (CH 2 ) 22 COOH or C24: 0 It is present in brain and myelin sheath of nerves. Also in peanut oil.

NB:  Saturated fatty acids are either: -Short chain fatty acid : fatty acids with less than 12 carbons -Long chain fatty acids (LCFA): fatty acids from 12 or more carbons  Fats rich in saturated fatty acids (e.g. butter) are solid in nature due to high melting point of saturated fatty acids.  Fats rich in saturated fatty acids increase the risk of high cholesterol level in blood.

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 CH 3 (CH 2 ) 5 10 CH= 9 CH(CH 2 ) 7 COOH It is present in all fats. 2- Oleic acid 18:1(9): present in all fats CH 3 (CH 2 ) 7 10 CH= 9 CH(CH 2 ) 7 COOH 3- Nervonic acid 24: 1(15): It is present in brain CH 3 (CH 2 ) 7 16 CH= 15 CH(CH 2 ) 13 COOH

b- Unsaturated FA containing more than one double bond (polyunsaturated): They include: - Linoleic acid 18:2(9,12): ω-6 fatty acid CH 3 (CH 2 ) 4 13 CH= 12 CH CH 2 10 CH= 9 CH(CH 2 ) 7 COOH - Linolenic acid 18:3(9,12,15): ω-3 fatty acid CH 3 CH 2 16 CH= 15 CH CH 2 13 CH= 12 CH CH 2 10 CH= 9 CH(CH 2 ) 7 COOH 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 CH 3 (CH 2 ) 4 15 CH= 14 CH CH 2 12 CH= 11 CH CH 2 9 CH= 8 CH CH 2 6 CH= 5 CH(CH 2 ) 3 COOH 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??

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) regardless of the chain length.

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 SourcesExamples Polyunsaturated fatscertain plant oils safflower, sesame, soy, corn and sunflower-seed oils, nuts and seeds Monounsaturated fatscertain plant oilsolive, canola and peanut oils, avocados

Triglycerides Triglycerides or called also Neutral fats: the most important and most abundant group of fats in nature. 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).

 Triacylglycerols (TAG) contain primarily fatty acids of at least 16 carbons (saturated or unsatuated).  The three fatty acids may be similar or different. In case if the three fatty acids differ, the fatty acid on carbon 1 is usually saturated, that on carbon 2 is unsaturated and that on carbon 3 is either saturated or unsaturated.  TAG 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). 

Digestion and Absorption of dietary TAG 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 3- Heat insulator, prevent heat loss

Digestion of dietary TAG: TAG are so large to be absorbed (to be taken efficiently by the mucosal cells of intestinal villi, and then to enter blood) so they must be degraded first. Enzyme that degrade fats is called: lipase In stomach: Digestion of TAG begins in stomach by acid stable lingual lipase (originates from glands at the back of tongue) or by gastric lipase secreted by gastric mucosa. These lipases are stable in acid medium (pH 4-6) and degrades TAG containing short chain fatty acids (less than 12 carbons) that are usually present in milk fat. So these lipases play important role in milk fat digestion in infants where the pH of stomach is much higher than in adults (pH= 5) due to the decrease in HCl.

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 HCO 3 - watery solution and Pancreatic 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 fat droplets and increase the 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

Role of Co-lipase in TAG digestion: Co-lipase is a protein secreted from pancreas. It bind lipsae in a ratio 1:1, causes a conformational change in the lipase to expose its active site that bind with TAG.

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. GlycerolGlycerol Fatty Acid 1 Fatty Acid 2 Fatty Acid 3 Lipase GlycerolGlycerol Fatty Acid 3 Fatty Acid 1 Fatty Acid 2 Triglyceride 2-Monoglyceride + 2 Free Fatty Acids 2 H 2 0

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 mucosal cells: 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 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??