Fatty Acid and Triacylglycerol Metabolism 1

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1 FATTY ACID Fatty Acid and Triacygycero Metaboism 1 Mobiization of stored fats and oxidation of fatty acids Lippincott s Chapter 16 G L Y C E R L FATTY ACID FATTY ACID TRIACYLGLYCERL CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH Fatty acid The pk a of carboxy group in fatty acid 4.8 So, at physioogica ph fatty acid exists as anion ω β α The hydrocarbon chain can be saturated or it may contain one or more doube bonds CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH=CH-CH 2 -CH=CH-(CH 2 ) 7 -C - Unsaturated Fatty Acid CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -C - 18:2Δ 9,12 or 18:(9,12) r CH 3 (CH 2 ) n C - Linoeic Acid ω6 1

2 Some fatty acids of physioogica importance Triacygycero (TAG) or FAT is the major energy reserve in the body It is more efficient to store energy in the form of TAG Why FAT not Carbohydrates? * More reduced: 9 kca per gram compared with 4 kca per gram of carbohydrates * Hydrophobic: can be stored without H 2 carbohydrates are hydrophiic 1 gram carbohdrates: 2 grams H 2 Why FAT not Carbohydrates? (Continued) Average adut has 10 Kg of Fat How many caories? 90,000 kca What is the mass of carbohydrates that produces 90,000 kca? 90,000 / 4 = 22.5 Kg How much water with it? 2

3 FATTY ACID as FUELS The major fue used by tissues but Gucose is the major circuating Fue Fue type Amount used/ Amount in 12 hours (kca) Fuids (kca) FA Mobiization of stored fats The need for hormona signa Fat is stored in Adipose tissue When needed a hormona signa reaches the adipocyte. Hydroysis of TAG Gucose TAG + 3 H 2 3 FA + gycero Hormones that activate the Hormone Sensitive Lipase Gucagon Epinephrine Norepinephrine ACTH 3

4 G y c o i s i s Fate of Gycero Guconeogenesis Gycero β xidation of Fatty Acids Fatty Acids are transported to tissues bound to abumin Degraded by oxidation at β carbon foowed by ceavage of two carbon units -CH 2 - -Cβ xidation of Fatty Acids (overview) CH 3 (CH 2 ) n -CH 2 -CH 2 - C - CH 3 (CH 2 ) n -CH 2 -CH 2 -C ~CoA Activation of Fatty Acids Joining F.A with Coenzyme A RC~SCoA (Thioester bond) FA + HSCoA + ATP FA~CoA + AMP + PP i CH 3 (CH 2 ) n -C-CH 2 -C ~CoA CH 3 (CH 2 ) n -C ~CoA + CH 3 -C ~CoA PP i + H 2 FA + HSCoA + ATP AMP + ATP 2 P i FA~CoA + AMP + 2 P i ADP + ADP 4

5 Activation of Fatty Acids (cont.) ATP conversion to AMP + 2 P i is equivaent to hydroysis of 2 ATP to 2ADP Enzyme: thiokinase (Acy CoA Synthetase) Location: - outer mitochondria membrane - mitochondria matrix ( for short and medium chain FA ) Transport of ong chain Acy CoA across inner mitochondria membrane Inner mitochondria membrane is impermeabe to Acy CoA Carrier system is required (Carnitine Shutte) It consists of: - Carrier moecue - Two enzymes - Membrane transport protein β xidation of Fatty Acids (overview) CH 3 (CH 2 ) n -CH 2 -CH 2 - C - 4 CH 3 (CH 2 ) n -CH 2 -CH 2 -C ~CoA CH 3 (CH 2 ) n -C-CH 2 -C ~CoA CARNITINE SHUTTLE CH 3 (CH 2 ) n -C ~CoA + CH 3 -C ~CoA 5

6 ??? 6

7 Energy Yied from FA xidation CH 3 -(CH 2 ) 14 -C-CoA Energy Yied from FA xidation (cont.) xidation of C 16 FATTY ACID 6 FADH 2 6 NADH 6 Acety CoA 7 FADH2 ====> 14 ATP 7 NADH ====> 21 ATP 8 Acety CoA ====> 96 ATP CH 3 -CH 2 CH 2 -C-CoA Activation of the Acid consumes 2 ATP Net 129 ATP moe per moe of C16 Fatty Acid CH 3 -C-CoA + CH 3 -C-CoA + FADH 2 + NADH *Sources: Carnitine - Dietary - Synthesis in Liver, Kidney * ther functions: - Export of branched chain acy groups from mitochondria -Excretion of acy groups that cannot be metaboized in the body Carnitine Deficiencies Secondary deficiencies: Liver disease, manutrition, requirements Congenita Deficiencies: Enzyme, uptake, tubuar reabsorption Abiity to use FA as a fue Accumuation of F.A and branched Acy groups in ces 7

8 xidation of unsaturated F.A: eic Acid CH3 (CH 2 ) 7 -CH = CH (CH 2 ) 7 -C~CoA 3 rounds f β oxidation 3 Acety CoA xidation of Unsaturated F.A: Linoeic Acid 18:Δ 9,12 3 Cyces of β oxidation Isomerase 12:Δ :Δ Acety CoA CH3 (CH 2 ) 7 -CH = CH CH 2 -C~CoA 12:cis Δ 3 isomerase Acety CoA CH 3 -(CH 2 ) 4 -CH=CH-CH 2 -CH 2 -C-CoA ( 10:Δ 4 ) Dehydrogenase CH3 (CH 2 ) 7 CH 2 -CH=CH-C~CoA 12:trans Δ 2 Reductase CH 3 -(CH 2 ) 4 -CH=CH-CH=CH-C-CoA CH 3 -(CH 2 ) 4 -CH-CH=CH-CH-C-CoA xidation of FA with odd number of carbons CH 3 -(CH 2 ) 13 -C~CoA Six Cyces of β oxidation???? װ CH 3 -CH 2 -C~CoA + 6 Acety CoA Propiony CoA??? 8

9 װ R-CH 2 -CH 2 C~CoA - E R-CH=CHC~CoA- FAD FADH 2 2 H 2 2 α xidation of Fatty Acids CH 3 CH 3 CH 3 (CH- CH 2 -CH 2 -CH 2 ) 3 -CH-CH 2 -C - CH 3 CH 3 H CH 3 (CH- CH 2 -CH 2 -CH 2 ) 3 -CH- CH-C - xidation of Very Long Chain Fatty Acid in Peroxisomes: E: FAD Containing xidase CH 3 CH 3 CH 3 (CH- CH 2 -CH 2 -CH 2 ) 3 - CH-C - + C 2 β xidation of Fatty Acids (overview) CH 3 (CH 2 ) n -CH 2 -CH 2 - C - Ketone Bodies CH 3 (CH 2 ) n -CH 2 -CH 2 -C ~CoA CH 3 (CH 2 ) n -C-CH 2 -C ~CoA CH 3 (CH 2 ) n -C ~CoA + CH 3 -C ~CoA 9

10 Synthesis: In Liver Precursor: Ketone Bodies Acety CoA At high rate during: -Fasting - Uncontroed Diabetes Meitus Net Reaction?? 2 Acety CoA Acetoacetate + 2 CoA Pamitic Acid Net Reaction 2 Acety CoA Acetoacetate + 2 CoA 8CoA Advantage (Purpose)? Gucose Acety CoA 7FADH 2 +7NADH Ketone bodies - For the iver - For the tissues xaoacetate CoA C 2 C 2 10

11 Increase Excretion in Urine as Sodium Sat Loss of water Dehydration Use of Ketone Bodies by Periphera Tissues: Skeeta Musce, Cardiac Musce and In Brain During Proonged Fasting (Starvation) Fue metaboism in starvation Amount formed or consumed in 24 hours (grams) Fue exchanges and consumption 3rd day 40th day Fue use by the brain Gucose Ketone bodies A other use of gucose Fue mobiization Adipose-tissue ipoysis Musce-protein degradation Fue output of the iver Gucose Ketone bodies