Metabolic Case III: Von Gierke Disease Flashcards
In normal fed state, what is the fuel that provides ATP in:
- Muscle?
- Adipose?
- Brain?
- Liver?
- Muscle: glucose
- Adipose: glucose
- Brain: glucose
- Liver: glucose
In normal short-term fasting state, what is the fuel that provides ATP in:
- Muscle?
- Adipose?
- Brain?
- Liver?
- Muscle: fatty acids
- Adipose: fatty acids
- Brain: glucose
- Liver: fatty acids
In normal long-term fasting state, what is the fuel that provides ATP in:
- Muscle?
- Adipose?
- Brain?
- Liver?
- Muscle: fatty acids, ketone bodies
- Adipose: fatty acids, ketone bodies
- Brain: glucose, ketone bodies
- Liver: fatty acids
What two processes produce glucose during normal fasting state?
- Glycogenolysis (short-term)
- Gluconeogenesis (short-term and long-term)
What enzyme is deficient in Von Gierke disease? What is this enzyme’s normal function?
Von Gierke disease: G6Pase deficiency
- Normally, G6Pase allows for glucose to be dephosphorylated and released into circulation to regulate blood glucose
In what two tissue types if G6Pase found?
- Liver
- Kidneys
NOT MUSCLE
What are the four metabolic abnormalities in Von Gierke disease?
- Hypoglycemia
- Lactic acidemia
- Hyperlipidemia
- Hyperalaninemia
If the Glucose-6P cannot be released from the cell in Von Gierke disease, what is its fate?
The trapped Glucose-6P will enter glycolysis and be broken down
What are the two ways by which F2,6BP levels are regulated?
1 bifunctional enzyme called PFK-2/FBPase-2
- High I/G ratio: PFK-2 is active, producing more F2,6BP
- Low I/G ratio: FBPase-2 is active, destroying F2,6BP (converts it back to Fructose 6P
How do high levels of Glucose 6P lead to glycolysis running in fasting Von Gierke patients?
High levels of Glucose 6P = high levels of Fructose 6P
- F2,6BP is produced from the Fructose 6P via PFK-2 due to substrate availability
- F2,6BP activates PFK-1 and glycolysis will run, even if I/G ratio is low
Why are their elevated levels of Pyruvate in fasting Von Gierke patients? Which of the four metabolic abnormalities does this result in, and why?
- Glycolysis is producing pyruvate (glucose > pyruvate)
- AA catabolism: low I/G ratio so gluconeogenesis runs and AAs are converted to pyruvate
Causes lactic acidemia when the NADH produced by glycolysis is converted back to NAD+ via pyruvate > lactate
How does Von Gierke disease result in hyperlipidemia?
High pyruvate levels from glycolysis leads to increased citrate production; this citrate is then used for
- Increased FA synthesis
- Speeding up of the TCA Cycle
Which three fed state processes are enabled during fasting state in a Von Gierke patient?
- Glycolysis: glucose from glycogenolysis is pushed into glycolysis due to inability to release Glucose 6P
- TCA Cycle priming: high pyruvate so both OAA and Acetyl CoA are produced
- De Novo FA Synthesis (increased Acetyl CoA)
Which two fasting state processes are inhibited during fasting state in a Von Gierke patient?
- Beta-oxidation because CPTI inhibited
- Ketogenesis because Acetyl CoA is instead used for FA synthesis, rather than to produce ketone bodies
Why are their increased circulating FAs in a fasting Von Gierke patient?
There is increased FA synthesis due to high Pyruvate and Citrate - these FAs are transported normally from the adipose to blood and taken up by the liver (only liver cells affected, not adipose)
