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Starvation

Starvation. Lecture 20. Lipolysis. Lipolysis. FAT. Fatty acids. Glycerol. P. inactive. active. PKA. TGL/HSL. Triacylglycerol lipase Hormone Sensitive Lipase. Lipolysis.  cAMP   lipolysis since cAMP activates PKA

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Starvation

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  1. Starvation Lecture 20

  2. Lipolysis Lipolysis FAT Fatty acids Glycerol P inactive active PKA TGL/HSL Triacylglycerol lipase Hormone Sensitive Lipase

  3. Lipolysis •  cAMP   lipolysis since cAMP activates PKA • Glucagon   lipolysis since glucagon causes an increase in cAMP • However, this is not the main cause of the increase in cAMP • The main cause of the increase of cAMP is the decrease in the rate of cAMP breakdown • Because of the decrease in phosphodiesterase activity

  4. Fatty acid oxidation • Lipolysis releases FAs into the blood • Note, even in starvation, GLUT-1 is still present in muscle • Even though a lack of insulin has led to GLUT-4s being endocytosed • So muscle is responsible for much glucose uptake • Need to preserve glucose: • Get tissues to stop using glucose, and use FAs instead • FAs will be oxidised to provide the acetyl CoA for the Krebs Cycle • But need to avoid oxidation of glucose, which is an irreversible reaction

  5. PDH • PDH = pyruvate dehydrogenase

  6. Glucose-Fatty Acid Cycle • In starvation we want PDH to be off • PDH kinase >> PDH phosphatase • PDH kinase is stimulated by acetyl-CoA • PDH is inactive when phosphorylated • Prevents wasteful oxidation of pyruvate • Pyruvate only made into lactate • FA released from WAT (from lipolysis), causes [FA]blood to increase and the uptake of FA into the muscle is also increased • Oxidation of FA (b-oxidation) switches PDH off by producing a lot of acetyl CoA. This stop glucose oxidation

  7. When PDH is off… • Pyruvate cannot be oxidized to acetyl CoA • Then there is only one fate for pyruvate in the muscle, --- to be converted into lactate by LDH • LDH = lactate dehydrogenase • Lactate can be taken up by the liver • Made into glucose by gluconeogenesis • Glucose recycling (glucose conservation) • Cori-cycle • Muscle Glucose  Pyruvate  lactate  liver glucose (via gluconeogenesis)  glucose to the bloodstream again • Gluconeogenesis can also happen from glycerol • Up to 30 g glucose per day can be made from glycerol

  8. In Early Starvation…

  9. Glucose Accounting • Glycerol (from lipolysis) is the only souce of DE NOVO gluconeogenesis • The lactate fuelled gluconeogenesis is just recycling • ~30g glucose from glycerol per day • But the brain needs ~120g/day, • not enough! • can brain glucose consumption be reduced?

  10. Lipolysis & b-Oxidation • After ~2-3 days of starvation, the rate of lipolysis approaches a maximum • FA released into bloodstream  [FA]blood  • There is a limit to how fast muscles will use FA • rate of b-oxidation depends on the demand of ATP by the muscles • Regeneration of CoA by Krebs cycle needed to keep FA oxidation going • BUT liver can do b-oxidation on FA even if there is no need for ATP • In the liver, CoA can be regenerated in a pathway other than the Krebs cycle

  11. Ketone Bodies • Ketone bodies – typically acetoacetate • Can be taken up & oxidised by the brain • Where they are split to 2 x acetyl CoA molecules • Tissues have to have mitochondria in order to use ketone bodies • Ketone bodies reduce brain glucose use from 120g/day to 30g/day • all 30g could be provided by glycerol…. • …. If it wasn’t for the use of glucose by the other carbohydrate-hungry tissues like skin, etc.

  12. Proteolysis • Hypoinsulinemia • Occurs when insulin level is really low • Especially for a long period (>48 h) • Proteins start to breakdown – PROTEOLYSIS • Gives rise to amino acids • Channeled to the liver for gluconeogenesis • Not all amino acids can be made into glucose • Glucogenic - can be made into glucose • Ketogenic - cannot be made into glucose • ~3g protein  1g glucose

  13. Ketosis and amino acid use

  14. Extended Starvation • After 2-3 days of starvation • Losses are 50-100g protein/day • Even though ketone bodies inhibit proteolysis and prevent protein being lost too rapidly • Proteins are lost from all tissues • Although inactive muscles tend to slightly preferentially degraded • From heart, liver, brain, etc, as well  may cause severe damage to body • Will reach equilibrium • where the amount of protein breakdown = the amount of glucose needed • But the loss of body protein is ultimately what kills us

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