Lecture 4: Metabolic Interplay Flashcards
What is the Randle cycle? Draw a diagram of it in the starved state. Draw a diagram of the switch to fat based metabolism.
The Randle cycle is a system in the body which allows glucose and fatty acid metabolism to control each other.
• During starvation, the body will switch from glucose to fat metabolism. This is in order to conserve glucose for the brain.
• The brain will be supplied with ketone bodies and glucose.
• During starvation, pyruvate dehydrogenase kinase is upregulated due to enhanced gene transcription.
• The brain isoforms have partial inhibition, while muscle isoforms have complete inhibition.
• In the fed state fatty acid breakdown in the muscle and liver is inhibited. Lipogenesis is encouraged and there is a switch to carbohydrate metabolism.
How is glucose-based metabolism encouraged in muscle?
Insulin mediates interactions between adipose and muscle.
• In adipocytes, insulin causes a decrease in fatty acid mobilisation. HSL is inhibited. The NEFA concentration is decreased. Fatty acid uptake in muscle decreases.
• In muscle, insulin causes recruitment of GLUT4. Glycolysis is upregulated. Pyruvate concentration increases which means more acetyl CoA and malonyl CoA. β oxidation occurs less.
What is CPT1? Draw a diagram of how it works.
CPT1 is a carnitine transporter used to transport long chain fatty acids into the mitochondrial matrix.
• CPT1 is regulated by malonyl CoA.
• Malonyl CoA is the 1st committed step in lipogenesis in the liver.
• It is used as a regulatory molecule to prevent simultaneous synthesis and breakdown of lipid.
• Muscle CPT1 is more sensitive to inhibition than liver CPT1.
How is ACC regulated? Draw a diagram of ACC regulation.
ACC is acetyl CoA carboxylase.
Liver
• It is used to convert acetyl CoA into malonyl CoA.
• Malonyl CoA downregulates CPT1. β oxidation is therefore downregulated.
• Glucagon and adrenaline upregulate AMPK and PKA in order to inactivate ACC with phosphorylation.
• Citrate can partially activate the inactive form.
Muscle
• Muscle does not synthesis lipids as it lacks FA synthase.
• ACC2 is used to regulate β oxidation in response to AMPK.
• ACC is phosphorylated on 2 serines by PKA (responds to adrenaline/glucagon) and AMPK (AMP/ATP ratio) respectively. PKA causes a small drop in activity, while AMPK causes a large drop in activity.
• Phosphorylation reduces the association constant for citrate and reduces its ability to activate ACC.
• Insulin rates raise citrate levels by increased glucose uptake. This activates ACC and inhibits fatty acid breakdown. Lipogenesis is promoted.
• Insulin also activates PP2A
What is the cori cycle? Draw a diagram.
The cori cycle is a system which regulates lactose in the blood.
• Anaerobically respiring cells like RBCs produce lactate.
• Lactate is converted into glucose.
What is the glucose-alanine cycle?
The glucose-alanine cycle is similar to the cori cycle.
• However, it does not allow amino acids to be used for glucose production.
• Carbon skeleton comes from pyruvate.
• But it does allow muscle glycogen to go back to the liver without G6P and it allows the amino group to export.
What does AMPK do?
AMPK responds to the internal energy state of the cell. It’s for short term energy regulation. It responds to ATP fluctuations. It isn’t involved in starvation because ATP levels will be stable.
• 2ADPs are added together to create ATP and AMP. This is done by adenylate kinase.
• It recruits GLUT4 to muscle cells.
• It inhibits ACC. Lipolysis is upregulated.
• It inhibits glycogen synthase.
• AMP activates GP-b and PFK allosterically. ATP inhibits them.
What does insulin do?
Insulin binds to the insulin receptor, a receptor tyrosine kinase.
• Activate PI3K pathway.
Liver
• It controls PEPCK in the liver, to control GNG.
• It activates PP1. This deactivates phosphorylase kinase. PP1 also activates glycogen synthase.
• Upregulates ACC by activating a phosphorylase (PP2A). Citrate also acts as an allosteric regulator. Decrease lipid metabolism.
• Insulin actives PP2A. It dephosphorylates bifunctional enzyme (BFE, aka PFK2), which drives glycolysis by turning F6P into F-2,6-BP. This activates PFK.
• It also activates SREBP1c, which activates GK and lipogenesis. GK increases glycolysis and glycogen synthesis.
Muscle
• GLUT4. Glucose uptake increases.
• It activates PP1. This upregulates glycogen synthesis.
• It activates PP2A. Activates ACC. Decrease lipid metabolism.
• It also increases glycolysis through PP2A.
Adipose
• Deactivates hormone-sensitive lipase.
• Activates lipoprotein lipase. Encourage fat uptake so they can be stored. It increases LPL transcription.
• It also increase all enzymes in the phosphatidic acid, which makes TAGs. You can’t make G3P in adipocytes, no glycerol kinase. You have to get it through G3PDH from DHAP, this comes from glucose metabolism.
• Insulin inhibits CPT1, which stops lipolysis. CPT1 puts fatty acids into the mitochondria. They, therefore, can’t be broken down.
What does glucagon do?
Liver
• Glucagon upregulates PEPCK transcriptionally.
• It phosphorylates BFE (PFK2) and downregulates glycolysis.
• It reduces succinyl CoA by reducing glycolysis.
• This upregulates HMG-CoA synthase, as succinyl-CoA is normally a repressor.
• It activates PKA. This affects the bicylic cascade of glycogen synthesis.
• PKA causes ACC activity to drop. Lipolysis is upregulated.
Adipose
• There are no liver glucagon receptors.
How do insulin and glucagon antagonise?
- PP2A.
- ACC.
- PEPCK. Transcriptional effects.
- BFE. PKA and PP2A have opposing effects.
- Succinyl CoA is raised by insulin and lowered by glucagon through effects on glycolysis. This affects HMG-CoA synthase (ketone bodies).
