FAT METABOLISM

1. FAT METABOLISM Dr. Gamal Gabr, College of Pharmacy

2. FAT METABOLISM • Carbohydrate metabolism and the metabolism of fat are directly connected and are under hormonal control.. • Many tissues will use glucose as a fuel substrate in a well-fed condition, while reserving the use of fat as a fuel for times of fasting and starvation and during prolonged exercise. • As levels of glucagon and adrenaline rise in response to falling levels of blood glucose, cAMP is generated by adenylatecyclasewithin the adipose cells, and protein kinase A is activated. • By phosphorylation, this kinase can activate hormone-sensitive lipase, the key enzyme regulating fat catabolism.

3. FAT METABOLISM • It hydrolyzes the two outside ester links that attach the long-chain fatty acids to glycerol in storage triglycerides.. • The last fatty acid ester link (found in the intermediate monoglyceride) is hydrolyzed by the enzyme monoglyceride lipase.. • Rising levels of insulin will promote the dephosphorylation and inactivation of hormonesensitive lipase. • Insulin also promotes an inhibition of adenylatecyclaseand a stimulation of the phosphodiesterase that inactivates cAMP.

4. FAT METABOLISM • The liberated free fatty acids leave the adipose cells and are transported to various tissues of the body, bound to the plasma protein albumin. • Thus, fasting will lead to an elevation of plasma free fatty acids. Fatty acids readily cross the plasma membrane of cells and are then activated by enzymes known as fatty acyl-CoA synthetases. • These reactions require ATP and CoA. CoA has an important sulfhydryl (-SH) group at the end of its structure. • The fatty acyl-CoA synthetasescreate a chemical link between the -SH group of CoA and the carboxyl of the fatty acid, generating a thioester linkage.

5. FAT METABOLISM • Fatty acyl-CoA molecules are generated outside the mitochondrial matrix. The mitochondria have two membranes, but the outer membrane has pores that allow relatively quick passage of smaller molecules (such as fatty acyl-CoA) into the intermembrane space.

7. The carnitine shuttle. • This mechanism employs two molecules of the enzyme carnitineacyltransferase located in the outer mitochondrial membrane (CAT I) and the inner mitochondrial membrane (CAT II) and a translocase in the inner mitochondrial membrane. • Initially, fatty acyl-CoA is converted into acylcarnitine, a molecule of much lower polarity that can be transported by the translocase into the mitochondrial matrix. • Here the acylcarnitine is converted back into fatty acyl-CoA for use in mitochondrial β-oxidation.

9. β-Oxidation of palmitoyl-CoA. In this mitochondrial catabolic path, there are four steps that work in sequence, ultimately to facilitate the removal of a two-carbon fragment (as acetyl-CoA) from this 16-carbon fatty acyl-CoA chain. • The steps are (1) dehydrogenation, (2) hydration, (3) dehydrogenation, and (4) release of acetyl-CoA. • This sequence of steps can be repeated until all the fatty acyl chain is converted into eight acetyl-CoA molecules. • During each sequence of β-oxidation, there is also the generation of NADH and FADH2, which can be used for ATP production via the electron transport chain and oxidative phosphorylation.

10. The fate of FADH2 , NADH and Acetyl-CoA • Each molecule of FADH2 2 molecules of ATP • Each molecule of NADH : 3 molecules of ATP. • Each molecule of acetyl-CoA can be oxidized to CO2 and H2O by the TCA cycle to yield: 12 molecules of ATP. • Activation process consume 2 ATP

11. The overall ATP yield For Fatty Acid = 16 Carbon atom The No. of Acetyl Co A = 8 molecule The No. of cycles = 7 Cycle Thus: 8 x 12 = 96 ATP 7 x 5 = 35 ATP 131 ATP – 2 ATP = 129 ATP