Production Of Ketone Bodies

Question 1

What are the 3 types of ketone bodies produced in the body? Where/how are these produced?

Answer 1

Produced in liver from acetyl~CoA:

1. Acetoacetate
2. Beta-hydroxybutyrate

Spontaneous decarboxylation of acetoacetate:
3. Acetone

Question 2

What is the normal plasma [ketone bodies]? Under which conditions can this change?

Answer 2

• Normally low concentration (<1 mmol/L).
• Can increase in:
  1. Starvation (2-10 mmol/L = physiological ketosis)
  2. Untreated type 1 diabetes (> 10 mmol/L = pathological ketosis)

Question 3

What property of ketone bodies allows their accumulation in the blood? What is the effect of this?

Answer 3

• Are water-soluble: allows high plasma concs.
• High plasma conc may cause acidosis (= ketoacidosis) as acetoacetate and beta-hydroxybutyrate are relatively strong organic acids.

Question 4

What is the characteristic smell of the breath of untreated type 1 diabetes? Why?

Answer 4

Smell of acetone (nail varnish remover) as is volatile and may be excreted via lungs.

Question 5

Describe the synthesis of ketone bodies. Where does this occur?

Answer 5

In liver MT.

1. Acetyl-CoA converted to HMG-CoA by synthase.
2. HMG-CoA converted to acetoacetate by lyase.
3. Acetoacetate can be further converted to beta-hydroxybutyrate or spontaneously convert to acetone.

Question 6

What can HMG-CoA be used to produce apart from ketone bodies?

Answer 6

HMG-CoA reductase can convert HMG-CoA to mevalonate, which then produces cholesterol.

Question 7

What determines the production of ketone bodies vs cholesterol?

Answer 7

The insulin:glucagon ratio.

• Low insulin:glucagon (due to decreased plasma [insulin])… activates HMG-CoA lyase and inhibits HMG-CoA reductase… activates ketone body formation.
• High insulin:glucagon… activates HMG-CoA reductase and inhibits HMG-CoA lyase… activates cholesterol synthesis.

Question 8

Why would statins be prescribed to a patient with high cholesterol levels?

Answer 8

Statins inhibit HMG-CoA reductase so inhibit cholesterol synthesis from HMG-CoA.

Question 9

How does low [glucose] promote ketone body production in the liver?

Answer 9

1. Low [glucose] causes release and beta-oxidation of FAs… produces high levels of NADH.
2. Low NAD+ substrate availability and NADH product inhibition inhibit 2 enzymes of TCA cycle (isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase).
3. So acetyl-CoA no longer used in TCA cycle… instead diverted to ketone body production.

Question 10

What is the point of ketone body production, in particular in early and later starvation/type 1 diabetes?

Answer 10

Ketone bodies = important fuel molecules that can be used by all tissues containing mitochondria including the CNS - are converted to acetyl-CoA in tissues, subsequently oxidised via stage 3 of catabolism.

1. In early starvation/diabetes, use of ketone bodies in muscle conserves circulating glucose for energy in brain.
2. In late starvation/diabetes, use of ketone bodies in muscle. Breakdown of muscle protein to amino acids which are used to form pyruvate in liver. Liver synthesises glucose from pyruvate (via gluconeogenesis) and glycogen (via glycogenolysis). So glucose can be used in brain.

Question 11

What is ketonuria? What is this a sign for?

Answer 11

Excretion of ketone bodies in urine when conc above renal threshold.
Sign of diabetes