1. Oxidation of Fatty Acids

2. BIOMEDICAL IMPORTANCE

3. Oxidation in – Mitochondria Biosynthesis in – Cytosol Utilizes NAD + and FAD as coenzymes generates ATP an aerobic process

4. fatty acyl chains acetyl-CoA units citric acid cycle generating ATP

5. Increased fatty acid oxidation – Starvation and of diabetes mellitus Ketone body production (ketosis) – Ketoacidosis Impairment in fatty acid oxidation – Hypoglycemia Gluconeogenesis is dependent upon fatty acid oxidation – Carnitine deficiency – Carnitine palmitoyltransferase – inhibition of fatty acid oxidationby poisons Hypoglycin

6. Fatty Acids Are Activated Before Being Catabolized – acyl-CoA synthetase (thiokinase) Long-chain fatty acids penetrate the inner mitochondrial membrane as carnitine derivatives Carnitine – β-hydroxy-γ-trimethylammonium butyrate

7. palmitoyl- CoA forms eight acetyl-CoA molecules

9. Overview of β-oxidation of fatty acids

10. The Cyclic Reaction Sequence Generates – FADH 2 – NADH

14. Oxidation of a fatty acid with an odd number of carbon atoms yields acetyl- CoA plus a molecule of propionyl-CoA Oxidation of Fatty Acids Produces a Large Quantity of ATP – 7*5 mol ATP – 8*12=96 mol ATP – 129 × 51.6* = 6656 kJ.

15. Peroxisomes Oxidize Very Long Chain Fatty Acids A modified form of β-oxidation formation of acetyl-CoA and H 2 O 2 the β-oxidation sequence ends at octanoyl- CoA

16. Oxidation of unsaturated fatty acids by a modified -oxidation pathway Formation of CoA esters β-oxidation until either a Δ 3 -cis-acyl-CoA compound or a Δ 4 -cis-acyl-CoA compound is formed (Δ 3 cis Δ 2 -trans-enoyl-CoA isomerase) Hydration Oxidation

19. KETOGENESIS Ketone bodies – acetoacetate and D(-)-3-hydroxybutyrate (β- hydroxybutyrate), acetone In the Liver

20. Interrelationships of the ketone bodies

21. Ketogenesis In Mitochondria Acetoacetyl-CoA – Starting material for ketogenesis

22. Pathways of ketogenesis in the liver

23. Ketone bodies serve as a fuel for extrahepatic tissues In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA

24. Formation, utilization, and excretion of ketone bodies

25. Transport and pathways of utilization and oxidation of ketone bodies in extrahepatic tissues.

26. Regulation of Ketogenesis AT THREE CRUCIAL STEPS – Control of free fatty acid mobilization from adipose tissue – the activity of carnitine palmitoyltransferase-I in liver – Partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle

27. Regulation of Ketogenesis Increase in the level of circulating free fatty acids – Uptake by the liver β-oxidized to CO 2 or ketone bodies or esterified CPT-I, fed state – Malonyl-CoA – β-oxidation from free fatty acids is controlled by the CPT-I gateway – [insulin]/[glucagon] ratio

28. Regulation of ketogenesis

29. Regulation of long-chain fatty acid oxidation in the liver

30. CLINICAL ASPECTS Impaired Oxidation of Fatty Acids – Hypoglycemia Carnitine deficiency Inadequate biosynthesis Renal leakage Losses hemodialysis – Symptoms Hypoglycemia Muscular weakness Inherited CPT-I deficiency

31. CLINICAL ASPECTS CPT-II deficiency – Affect primarily skeletal muscle Inherited defects in the enzymes of β-oxidation and ketogenesis Jamaican vomiting sickness – Hypoglycin Inactivates acyl-CoA dehydrogenase – Inhibiting β-oxidation Dicarboxylic aciduria – Medium-chain acyl-CoA dehydrogenase

32. CLINICAL ASPECTS Refsum’s disease – accumulation of phytanic acid Blocks β-oxidation Zellweger’s (cerebrohepatorenal) syndrome – absence of peroxisomes

33. Ketoacidosis Results From Prolonged Ketosis Higher than normal quantities of ketone bodies – Ketonemia – Ketonuria Diabetes mellitus Starvation – Depletion of available carbohydrate coupled Mobilization of free fatty acids Nonpathologic forms of ketosis – High-fat feeding – after severe exercise