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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

Starvation

Lecture 20

lipolysis
Lipolysis

Lipolysis

FAT

Fatty acids

Glycerol

P

inactive

active

PKA

TGL/HSL

Triacylglycerol lipase

Hormone Sensitive Lipase

lipolysis1
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
fatty acid oxidation
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
slide5
PDH
  • PDH = pyruvate dehydrogenase
glucose fatty acid cycle
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
when pdh is off
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
glucose accounting
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?
lipolysis b oxidation
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
ketone bodies
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.
proteolysis
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
extended starvation
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