FORM & FUNCTION (Ketone Bodies) Flashcards
Acetyl-CoA:
-mitochondria can be converted into citrate or ketone bodies
Ketone bodies;
-small, water-soluble fatty acid produced by acetyl-CoA in the LIVER
>soluble because they have so little carbons
Ex. acetone, acetoacetate, D-b-hydroxybutyrate
Metabolically active ketone bodies;
-acetoacetate
-beta-hydroxybutyrate
D-b-hydroxybutyrate:
-aliphatic hydrocarbon and carboxylic acid
When are ketones synthesized?
-glucose deficiency
>prolonged starvation
>diabetes mellitus
>CHO restriction (Atkin’s diet)
Steps for when ketones are synthesized:
1.Depletion of CHO (primary metabolic fuel, for the brain)
2.Activation of FA oxidation to generate ATP
3.BUT, when glucose is low, oxaloacetate is used for gluconeogenesis
>Don’t have any oxaloacetate for FA’s to go into TCA
>Acetyl CoA cannot be converted to citrate to enter the TCA
4.Excess acetyl-CoA is shuttled into ketogenesis
>Circulate in the blood to feed other issues
Ketone as metabolic fuel:
-utilized by most aerobic tissues except the LIVER
-water-soluble equivalent of FA: can cross BBB and placental barrier
Why are ketones important as a metabolic fuel?
-FA while high in energy, must be bound to albumin to be soluble
-FFA-albumin cannot cross the BBB or placental barrier
*important source of fuel for brain and fetus during starvation in lieu of glucose
Ketone bodies: liver:
-liver doesn’t/can’t use any of the ketone it makes (goes to all other tissues)
Ketogenesis steps:
- 2 Acetyl-CoA are condensed to form acetoacetyl-CoA
- A 3rd Acetyl-CoA is added to from HMG-CoA by HMG-CoA synthase (rate-limiting step)
- HMG-CoA is degraded to yield acetoacetate and Acetyl-CoA
HMG-CoA synthase:
-inhibited by insulin (nutrient rich state)
-promoted by glucagon (nutrient starved state)
When NADH is in abundance (ketogenesis):
-acetoacetate can be converted to beta-OH-butyrate
-occurs when beta-oxidation is high
*high rate of fat breakdown increases beta-oxidation and elevates NADH
*both acetoacetate and beta-OH-butyrate are soluble compounds that cross BBB
Ketone dipstick:
-urine dipstick for ketone analysis will ONLY detect acetoacetate and not beta-hydroxybutyrate
-quick results, but can underestimate true ketone level
Ketone metabolism overview;
-provide source of acetyl-CoA in absence of glucose
-oxaloacetate is available in the brain (or other tissues) to couple with acetyl-CoA (gluconeogenesis primarily takes place in the liver)
*reduces the pressure to undergo gluconeogenesis (-6ATP)
Ketone prioritized to vital organs:
-brain (alternative metabolic fuel)
-muscle with physiological functions
>heart
>diaphragm
>smooth muscle in digestive tract
>myometrial smooth muslces
*can’t be used by RBC: don’t have mitochondria (can’t do aerobic respiration)
Negative effects of ketone:
-acetoacetate and beta-hydroxybutyrate are naturally acidic (pKa=3.5)
>donating H+ into the blood
>can lead to ketoacidosis (over longer periods of time)
-acetone (less severe)
Ketoacidosis:
-ketosis from diet: 1-6mM ketone in blood
-ketoacidosis in unmanaged diabetes: 15-30mM ketone in blood
Metabolic acidosis:
-H+ removes HCO3-, resulting in increased anion gap
*excess ketones lead to metabolic acidosis
>respiratory compensation (hyperventilate to reduce Pco2)
Increase in anion gap:
-due to decrease in HCO3-
-total charge is still neutral
>acetoacetate/beta-hydroxybutyrate also increased
Acetone: negative effects:
-third type of ketone
-metabolically inert
-spontaneous conversion of acetoacetate when concentration is high
-highly volatile, high vapour pressure
-excreted via urine or exhaled
-has a sweet or fruity smell, in the breath or urine of ketotic patients
