Ketone bodies

Question 1

After how many days of fasting does gluconeogenesis fall?

Answer 1

~2days

Question 2

Why cant prolonged fasting be fuelled by gluconeogenesis?

Answer 2

Amino acid pool would deplete and muscles would atrophy

Question 3

What state are KB made in?

Answer 3

Fasting state

Question 4

Are KB sourced from diet?

Answer 4

No, they are made in the body

Question 5

Can you store KB?

Answer 5

No, they are made and used on demand

Question 6

Describe the simple structure of KB?

Answer 6

Small 4 Carbon molecules

Water soluble

Question 7

What are the metabolically active KB?

Answer 7

Acetoacetate and β-hydroxybutyrate

Question 8

What about acetone can be noticed?

Answer 8

Its fruity smell on the breath

Question 9

How can you use KB as a fuel source?

Answer 9

Make them (in the liver) - ketogenesis

Degrade them (at site of use) - ketolysis

Question 10

Where does ketogenesis occur?

Answer 10

In the liver mitochondria

Question 11

What steps predate ketogenesis (and are needed for ketogenesis) ?

Answer 11

Low insulin / elevated glucagon

HSL activated

NEFA released from TAG stores

NEFA distributed to the liver

FA activated (fatty acyl CoA)

FA into mitochondria (carnitine shuttle)

Oxidation to acetyl CoA

Question 12

How are NEFA carried to the liver?

Answer 12

VLDL/Albumin

Question 13

In the non-starving state what happens to acetly CoA in the mitochondria?

Answer 13

Acetyl CoA generated from beta-oxidation will enter the TCA cycle by combining with oxaloacetate.

Question 14

When starving why does acetyl CoA not enter the TCA cycle?

Answer 14

Low availability of oxaloacetate

In a fasted state, oxaloacetate is consumed to form glucose by the gluconeogenic pathway (which is driven by low blood glucose.)

Question 15

When the acetyl CoA cannot enter the TCA cycle what happens to it?

Answer 15

Acetyl CoA is diverted to the production of the ketone bodies, acetoacetate and beta-hydroxybutyrate.

Question 16

Describe the first step of ketogenesis

Answer 16

Two molecules of acetyl CoA condense to form acetoacetyl CoA. This reaction is catalysed by thiolase.

Question 17

Describe what happens to acetoacetyl CoA?

Answer 17

Acetoacetyl CoA combines with a third molecule of acetyl CoA and water to give HMG-CoA via the enzyme HMG CoA synthase.

Question 18

How is acetoacetate produced from HMG-CoA?

Answer 18

HMG-CoA is then split by HMG CoA lyase into acetoacetate and acetyl CoA.

Question 19

How is beta-hydroxybutyrate formed?

Answer 19

Beta hydroxybutyrate is formed via the reduction of acetoacetate by beta hydroxybutyrate.

Question 20

How is beta-hydroxybutyrate production controlled?

Answer 20

Depends on the NADH/NAD+ ratio

Question 21

How is acetone produced?

Answer 21

The slow, spontaneous decarboxylation of acetoacetate produces acetone.

Question 22

What happens to the KB produced in the liver?

Answer 22

Ketone bodies are transported out of the liver mitochondria and into the blood via transport proteins.

Through circulation they are distributed to target tissues

Question 23

What happens to KB at target tissues?

Answer 23

They can be reconverted into acetyl CoA during ketolysis which can be used as fuel and enter the TCA cycle.

Question 24

What tissues prefer KB over glucose in normal homeostatic conditions?

Answer 24

Cardiac muscle

Renal cortex

Question 25

What is the main importance of KB?

Answer 25

Supply the tissues that require it as a secondary source, when lacking other nutrients.

Resource to the brain in periods of starvation when glucose - its major fuel - is at insufficient levels.

Question 26

Why cant ketolysis occur in the liver?

Answer 26

Liver doesn’t express the enzyme 3-ketoacyl coA transferase to process ketone bodies,

Question 27

Why is it beneficial that the liver doesnt undergo ketolysis?

Answer 27

Prevents futile cycling

Question 28

What is the first step of ketolysis?

Answer 28

Acetoacetate is activated by the transfer of CoA from succinyl CoA in a reaction catalysed by 3-ketoacyl CoA (present in non-hepatocytes).

Forms acetoacetyl CoA

Question 29

What happens to the acetoacetyl CoA in ketolysis

Answer 29

Acetoacetyl CoA is cleaved by thiolase to yield two acetyl CoA molecules that can enter the TCA cycle and combine with oxaloacetate.

Question 30

How is Beta-hydroxybutyrate converted back to acetoacetate?

Answer 30

Produces NADH

Beta hydroxybutyrate dehydrogenase