1.07 - Ketone Bodies & Cholesterol

Question 1

Describe the use of alternate fuels in various tissues

Answer 1

Brain cells do not utilise β-oxidation of fatty acids
Heart muscle cells and the renal cortex prefer an alternate fuel
Skeletal muscles may also adapt to this alternate fuel
This mystery fuel are Ketone Bodies

Question 2

Discuss ketone bodies and the liver

Answer 2

The “choice” is available in hepatocytes
Ketone bodies are exported from the liver to other tissues
Increased production when OAA is diverted from the TCA cycle towards gluconeogenesis in hepatocytes
β-hydroxy-butyrate & acetoacetate (KB’s) are exported
In starvation the brain may get 5% of its fuel source from ketone bodies
The liver is an exporter but not a user –> “altruistic organ”

Question 3

List the steps in the synthesis of Ketone Bodies

Answer 3

2x AcetylCoA –> Aceto-AcetylCoA + CoA
Aceto-AcetylCoA + AcetylCoA –> HMG-CoA + CoA
HMG-CoA –> Aceto-Acetate + Acetyl CoA
Aceto-Acetate –> Acetone + CO2
Aceto-Acetate –> Beta-hydroxy butyrate + NAD+

Main site of synthesis is the liver
Mitochondrial enzymes
Acetone is volatile (diabetic breath)

Question 4

Discuss the utilisation of ketone bodies as a fuel

Answer 4

3 step process
Mitochondrial
The enzyme Keto-acyl-CoA transferase not used in synthesis 
  - Not found in liver
  - Liver is an exporter and not a user

Question 5

List the steps in Ketone Body breakdown for use as a fuel

Answer 5

Beta-hydroxy-butyrate + NAD+ –> Acetoacetate + NADH
Aceto-acetate + Succinyl-CoA –> Aceto-Acetyl-CoA + Succinate
Aceto-Acetyl-CoA –> 2x Acetyl-CoA
Acetyl CoA –> TCA Cycle

Question 6

Describe the association between ketone bodies and starvation

Answer 6

Production of ketone bodies requires continued β-oxidation –>Cellular CoASH levels are limited (formed during ketone body synthesis)
Acetyl-CoA must be processed
Primary route is via the TCA cycle but there are reduced TCA cycle intermediates → elevated Ketone body formation

Question 7

Describe the association between ketone bodies and untreated diabetes

Answer 7

Insulin response is low
Glucose not taken up for energy provision or fat production
No Malonyl-CoA production
β-oxidation not inhibited & [Acetyl-CoA] is increased –> Increased ketone bodies

Question 8

What are the consequences of unregulated ketone body synthesis

Answer 8

Leads to accumulation acetoacetate and beta-hydroxy-butyrate –> plasma pH acidifies. This is known as ketosis.
Extreme ketosis can cause death.

Question 9

What are the roles of Cholesterol

Answer 9

Membrane structure
Hormone composition
Fat emulsification

Question 10

Describe cholesterol biosynthesis

Answer 10

27 carbon compound
Built from carbon units of acetyl-CoA
All cells capable of cholesterol biosynthesis
Process occurs in cytosol and transferred to the endoplasmic reticulum

Question 11

What are the four main steps in cholesterol biosynthesis?

Answer 11

1. Mevalonate synthesis from acetyl-CoA
2. Isoprene formation
3. Condensation to squalene (use of 6 isoprenoids)
4. Ring closure (Squalene to Cholesterol)

Question 12

Describe the stages in the first step of cholesterol biosynthesis

Answer 12

Three molecules of Acetyl-CoA used
Reaction sequence identical to ketone body synthesis
BUT reactions are cytosolic
HMG-CoA reductase catalyses the committed step
Enzyme attached to ER membrane
Irreversible reaction
Regulated step of the pathway

Question 13

List the steps in the first stage of cholesterol biosynthesis

Answer 13

Acetyl-CoA –> Acetoacetyl-CoA +CoA
Acetoacetyl-CoA + AcetylCoA –> HMG-CoA + CoA

HMG-CoA + 2NADPH –> Mevalonate + 2NADP+
Enzyme: HMG-CoA reductase (attached to ER membrane)
Regulated step

Question 14

Describe the biological regulation of cholesterol synthesis

Answer 14

Biosynthesis is tightly regulated
Cellular [cholesterol] is the key factor
Enzyme = HMG-CoA reductase
•Amount and activity altered

Question 15

Discuss the pharmacological regulation of cholesterol synthesis

Answer 15

Familial hypercholesterolemia
o High blood [cholesterol]
o Leads to atherosclerotic plaque development
Cause in an inability to take up LDL-associated cholesterol from the blood
o Consequently, low intracellular [cholesterol] does not inhibit synthesis
o Results in an imbalance in total cholesterol
Statins (e.g. lovastatin) are used to reduce endogenous cholesterol synthesis
o Statins inhibit HMG-CoA reductase
o Can reduce cholesterol level by 30%
o Combine with resins (absorb bile acids) and low cholesterol diet

Question 16

What are the fates of Cholesterol

Answer 16

Esterification (increases hydrophobicity –> transportation)
Bile Comonents (Cholic Acid + Glycocholic Acid)
Hormones

Question 17

What are the hormones produced from cholesterol?

Answer 17

Progesterone
Cortisol
Testosterone
Estradiol

Question 18

Discuss the purpose of cholesterol being convert to Bile components

Answer 18

Cholic Acid	
  Bile salts are polar versions of cholesterol
  Synthesised in the liver, stored in gall bladder
  Released to bile
  Detergent like properties
  Solubilise dietary lipids
Glycocholic Acid
  Bile salts may be conjugated
  Detergent like properties
  Solubilise dietary lipids