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)
Why is HSL activity increased in a fasting Von Gierke patient?
Fasting Von Gierke patients have a lower I/G ratio and HSL is activated by low I/G ratio via Epi
- Lower I/G ratio = more Epi = highly active HSL
How is beta-oxidation of FAs affected in a fasting Von Gierke patient?
Beta-oxidation of FAs is inhibited
- Pyruvate is converted to Acetyl CoA which in turn produces Malonyl CoA, the inhibitor of CPTI (rate limiting enzyme of beta-oxidation)
Why are hepatomegaly and nephromegaly common in Von Gierke patients?
Increased glycogen storage due to inability to convert glycogen to glucose
How does Von Gierke disease result in hyperalaninemia? What is the alanine converted to in the liver?
During fasting, alanine is released from the muscle as a way to transport N from BCAA catabolism to the liver
- In the liver, alanine is converted to either Pyruvate or NH3 (used in Urea Cycle)
What is the recommended diet for Von Gierke disease, and why?
Complex carbohydrates because these result in slow absorption of glucose in the body
Why is a low carb/high protein diet NOT recommended for Von Gierke disease?
Low carb/high protein diet would start glycogenolysis and gluconeogenesis, neither of which are running due to the liver thinking it is in fed state
