Lipolysis

1. Lipolysis

2. Lipolysis • Largest storage form of energy • Provides energy at the slowest rate • Stored: • adipose tissue • muscle • Brain, CNS, abdomen, etc. • Use of lipids spares glycogen during prolonged work

3. Lipids • Substance that is water insoluble, but soluble in organic solvents • Most are Non-polar (uncharged) • Important in a variety of roles

4. Cholesterol: • Sterol: Comes from diet or is synthesized in liver • Important: Cell membrane structure • Steroid hormone synthesis • Testosterone, Estrogen, Corticosteroids

5. Derived from incomplete Fat metabolism • Formed from excess Acetyl-CoA • Kreb’s cycle slows due to low CHO stores • 2 Acetyl-CoA molecules • Acetoacetyl-CoA • Acetoacetate • D-β-Hydroxybutyrate • Last two used for energy

6. Exception to “polarity” rule • Found in cellular membranes • Profers some “selectivity” to the membrane

7. Fat digestion • Triglycerides • Biggest percentage • Cholesterol and phospholipids • Digested in small intestine • Bile: emulsifying agent

8. Pancreatic lipase • Breaks down fat globule (Micelles) • Monoglycerides, FFA and glycerol • Taken up by small intestinal cells • Repackaged with intestinal cells as Chylomicrons • Released into lymph • Different from carbs, most go to heart first

9. Chylomicrons and lipoproteins • Two mechanisms of fat clearance from blood • Transport to liver • Uses fats for fuel • Converts to lipoproteins • Mix of trigs, phospholipids, cholesterol and protein • Protein allows transport in blood

10. Lipoproteins • Classified by density • VLDL: mostly triglycerides • LDL: mostly cholesterol • HDL: mostly protein

11. Uptake of fatty acids: Lipoprotein lipase • In capillary/cell interface of most tissues • This enzyme facilitates uptake of FFA from blood after a meal • Hormone sensitive lipase • Essentially same enzyme • Breaks down intracellular lipids in fasted state

12. Lipid utilization during exercise • Primarily used: • Rest, prolonged low-moderate intensity exercise, recovery from exercise • Complicated • Multi-step • Mobilization • Circulation • Uptake • Activation • Fatty-acyl-CoA • Translocation • Β-oxidation • Mitochondrial oxidation

13. Mobilization • HSL • Breaks down stored triglycerides • Stimulated by catecholamines (rapid phase) • Growth hormone (prolonged phase) • Triglycerides carried in blood by albumin

14. Circulation and uptake • FFA circulated in blood bound to albumin • Uptake • Directly related to circulating concentration • Rate of blood flow • Increased flow, increased delivery, increased uptake and utilization

15. Activation and translocation 1 • FFA are taken up by FABP • FAT (fatty acid transporter) • Brings the FFA into the cell 3)Attachment of FA to CoA molecule • Fatty acyl-CoA • Outer mitochondrial membrane 4) Translocation • Into mitochondrial matrix • Carnitine and CAT1 and CAT2 2 3 4

16. β-oxidation • Breaks down FA-CoA to acetyl-CoA (2C fragment) • Starts the process of fatty acid oxidation • 16C FA requires: • 7 cycles of β-oxidation • Each cycle produces 1 Acetyl-CoA, 1 NADH and 1 FADH2 • So 16C FA produces how many ATP? • 8 acetyl-CoA, 7 NADH, 7 FADH2 • WHY 8 Acetyl-CoA? • Each acetyl-CoA = 12 ATP (3 NADH, 1 FADH, 1 ATP) • Activation costs 2 ATP (equivalent, one ATP to AMP)

17. Oxidation of fatty acids • After β-oxidation • Acetyl-CoA • Enters Kreb’s cycle • NADH and FADH go to electron transport chain

18. Free fatty acids: rest and exercise • Opposite of CHOs • Fasted state raises FFA • Most pronounced during low-to-moderate intensity exercise

19. Intramuscular triglycerides • Stored in muscle much like glycogen • Hormone Sensitive Lipase • Breaks down trigs within cell • Hard to quantify utilization • Concomitant use by cell and uptake from blood

20. Intramuscular lipolysis • Perhaps used in type I fibers • Results suggest that they are used primarily during recovery from exercise

21. Lipid oxidation in muscle • FFA are taken up by the muscle • Training increases this ability • Intramuscular TG • Probably used when glycogen becomes depleted • Most likely used in recovery • Used to a great extent by diving mammals

22. Tissue specific fat metabolism • Heart and liver specially adapted to fat utilization • Brain, RBCs use glucose almost exclusively • Muscle: in between • Type IIb: use relatively little fat • Type I: use much more fat • Muscle mitochondrial adaptations • Much greater than those associated with the cardio-circulatory system (i.e. heart, capillary vol., etc.) • Increases ability to use fat (particularly when glycogen is low) • Note how FFA are utilized much more quickly when enzyme content is doubled

23. Crossover concept • Biggest factor in Fuel selection • Power output • Rest • Mostly fat used • Exercise • Depends on intensity • Training • Can shift fat curve to left • Sympathetic nervous system stimulation • Shifts fat curve right

24. Crossover concept • Note that it is 50% fat-50% CHO at very low power output (~30% Vo2 max) • As power output rises, fat oxidation slows due to: • The complexity of the FA oxidation process • Reduced blood flow to inactive tissues • Sympathetic nervous system stimulation (which increases CHO utilization) • Endurance training only affects the percentages slightly

25. Glycerol • Marker of FFA mobilization from fat stores • This data suggest slightly greater mobilization after training at 45% • FFA • Simultaneously mobilized into blood and taken up by the tissues • Why are blood levels of FFA lower after training?

26. Glycerol • Rate of appearance • Measure of mobilization • Note that mobilization is greater following training • FFA • Appearance and disappearance • Measure of turnover • Note that prior to training • FFA turnover falls with intensity • After training • Pattern is different

27. Ketosis: Fuel source? • Under starvation conditions • When carbohydrate use is minimal • Reduces protein catabolism for energy needs • Ketone bodies • Acetoacetate, • β-hydroxybutyrate • Acetone

28. Can be taken up by brain • Converted to acetoacetate • Converted to acetyl-CoA and oxidized • Problems?