Starvation
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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

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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


Starvation

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


In early starvation

In Early Starvation…


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


Ketosis and amino acid use

Ketosis and amino acid use


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


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