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1 number 20 Done by Corrected by Rana Ghassan Doctor

2 Only 4 questions in the mid-term exam are based on the 4 lectures to be given by Dr Faisal. Dr Faisal will give us 10 lectures, the first 4 are included in the mid. In this lecture we will begin discussing fat metabolism What is a Triacylglycerol (TAG) Triacylglycerol refers to a group of compounds in which glycerol forms three ester bonds, each one with a fatty acid. The triacylglycerols differ according to which fatty acids were included in the structure. So, tri refers to the three fatty acids, acyl refers to the varying lengths of the hydro-carbon chains in the fatty acids and glycerol refers to glycerol itself. Structure of Fatty-acids Each fatty acid consists of a hydro-carbon chain (of varying lengths) and a single terminal carboxyl-group. In numbering the carbons, the carbon of the carboxyl group takes #1, the one next to it takes #2 and so on. Another way of numbering is using the Greek alphabet; the first carbon after the carboxyl group takes the letter α, the second takes β, the third takes ϒ, the fourth takes δ(delta), the fifth takes ε (epsilon) and so on till reaching the last carbon which always takes ω (omega) regardless of whether we actually reached omega or not. The hydro-carbon chain of the fatty acid can be unsaturated (has one or more double bonds). These double bonds are of great importance biochemically so we need to clearly give information about their presence and position, therefore, another method of describing fatty acids was developed. For example, linoleic acid, a fatty acid with two double bonds, one between carbon number 9 and carbon number 10 and the other between carbons number 12 and 13, linoleic acid has 18 carbons in total, then linoleic acid s information are displayed in this way: 18:2Δ⁹ ¹²or 18:(9,12). Another way is to start counting from carbon ω till the first carbon with a double bond, so, for linoleic acid its last double bond ends at carbon #13, counting from the other side that would be #6 so it is grouped under the ω-6 fatty acids. In the following list you need to memorise the fatty acids (everything, structure, name etc.) from butyric acid to arachidonic acid (inclusive):

3 Side Notes: Formic acid, acetic acid and propionic acid are not considered fatty acids, they are grouped under the carboxylic acids. Often, fatty acids are named according to where they were extracted from first, e.g. butyric acid was extracted from butter. The double bonds in the fatty acids are never consecutive, there always must be a non-double bond(methylene group CH 2) between each two double bonds, that is why the double bonds positions are always three carbons apart (e.g. 9,12,15 or 8,11,14 etc.) Triacylglycerols (Fats) They are the major energy reserve in the body. The triacylglycerols in your body are enough to let you survive approximately for two months without any food. Storing energy in the form of fat is more efficient than storing it as carbohydrates because fats are more reduced (they have far less oxygen atoms than carbohydrates which are oxygen rich) so can produce more energy when they get oxidised: Oxidation of 1 gram of fat produces 9 kcal, while the oxidation of 1 gram of carbohydrates produces only 4 kcal (that is 2.25X). Another advantage for fats as storage molecules is that they are hydrophobic, this means that they can be stored without the need for any extra water making the total mass stored less than that of carbohydrates (they are hydrophilic) considerably (for each 1 gram of carbohydrates stored 2 grams of water need to be stored as well!).

4 If a person has 10 kg (usually people have more) of fat in his body that means it can produce 90,000 kcal, his daily need is about 2,000 kcal, which means that his fat alone would sustain him for 45 days with no food at all. If we were to produce the same energy, but using carbohydrates then we need 22.5 kg of carbohydrates and with each gram of carbohydrates 2 more from water then we would need a total amount of 67.5 kg!! (In the adipocytes in the adipose tissue, fat makes up around 90% of the cell with no water needed). Fatty Acids as Fuels The fatty acids are the preferable fuel for most of our tissues, but the tissues that use most of the fatty acids are the cardiac muscles, the skeletal muscles and the liver. Other tissues do use fatty acids, but only in small amounts as their energy needs are way less (e.g. bones are structural components so have a very slow metabolism so need low amounts of energy). Brain and the RBCs (no mitochondria in RBCs) however, are totally dependent on glucose. An example to show how most of the body prefers fatty acids: at any time the amount of fatty acids present in the extracellular fluid is 0.4g only while that of glucose is 20g. Still, 60g of the fatty acids are used (the used up amounts are remade/more come from the stores) (that is 540kcal) while only 70g of glucose are used (that is 280 kcal) in 12 hours, so, most of the energy in the ECF is produced from the fatty acids. Mobilisation of Stored Fat This step needs a hormonal signal. Fat is stored in adipocytes and when a hormonal signal is received the adipocyte gets an order to produce fatty acids, so it hydrolyses TAGs using the hormone sensitive lipase enzyme producing three fatty acids and a glycerol (hormones that can do the job: glucagon (released when blood glucose is low), epinephrine and norepinephrine and ACTH (Adrenocorticotropic hormone, stimulates adrenal-cortex gland (also known as the supra-renal gland) (all of the three hormones are produced in response to energy requiring situations or stressful conditions).

5 The hormonal signal initiates the production of camp which activates protein kinase which, in turn, activates the hormone sensitive lipase by phosphorylating it. The hydrolysis process happens sequentially removing one fatty acid at a time. Triacylglycerol Diacylglycerol + fatty acid monoacylglycerol + fatty acid glycerol + fatty acid (all the reactions use the same hormone sensitive lipase enzyme). Fate of Glycerol Glycerol leaves the adipocytes, enters the blood and then to the liver. In the liver the enzyme glycerol kinase converts glycerol, using ATP, to glycerol phosphate. Glycerol phosphate is then converted to dihydroxyacetone phosphate (DHAP) using the enzyme glycerol-phosphate dehydrogenase. The DHAP is an intermediate of both gluconeogenesis and glycolysis so it can proceed to either of these two pathways. However, gluconeogenesis is the more preferred pathway as in this situation blood glucose is low (why was the fat mobilised if not?). Producing glucose allows us to maintain blood glucose and reserve glucose for the cells that need it most, the RBCs and the brain cells, the liver can produce its energy from fatty acids oxidation (fatty acids cannot be converted to glucose). Side note: glycerol makes around 5-6% of the triacylglycerol. The β-oxidation of Fatty-acids It is called β oxidation because the oxidation occurs at the carbon named β (carbon #3 in normal naming). The fatty acids are insoluble in water, so, in the blood they are carried with albumin. The β-oxidation process can be divided to two parts: oxidation at the β-carbon and cleavage between the α and β carbons. Firstly, a coenzyme A molecule binds to the carboxyl side of the fatty acid, then the β-carbon is oxidised producing the carbonyl group. Then the cleavage

6 occurs producing acetyl CoA and an acyl CoA (any number of carbons). The acyl CoA goes back to the β-oxidation reaction for further break down and for more acetyl CoA molecules to be produced. This continues till no more acetyl CoA can be produced. Side note: if a molecule with any number of carbon atoms is called acyl then if we add a keto-group to such a molecule it is called keto-acyl.