Presentation on theme: "Starvation Lecture 20. Lipolysis FATFatty acids Glycerol Lipolysis inactive active P TGL/HSL Triacylglycerol lipase Hormone Sensitive Lipase PKA."— Presentation transcript:
Starvation Lecture 20
Lipolysis FATFatty acids Glycerol Lipolysis inactive active P TGL/HSL Triacylglycerol lipase Hormone Sensitive Lipase PKA
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 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
PDH PDH = pyruvate dehydrogenase
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 ( -oxidation) switches PDH off by producing a lot of acetyl CoA. This stop glucose oxidation
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…
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 & -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 -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 -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 – 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 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
Extended Starvation After 2-3 days of starvation –Losses are g 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