1.07 - Ketone Bodies & Cholesterol Flashcards

1
Q

Describe the use of alternate fuels in various tissues

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Discuss ketone bodies and the liver

A

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”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

List the steps in the synthesis of Ketone Bodies

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Discuss the utilisation of ketone bodies as a fuel

A
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe the association between ketone bodies and starvation

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Describe the association between ketone bodies and untreated diabetes

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the consequences of unregulated ketone body synthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the roles of Cholesterol

A

Membrane structure
Hormone composition
Fat emulsification

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Describe cholesterol biosynthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the four main steps in cholesterol biosynthesis?

A
  1. Mevalonate synthesis from acetyl-CoA
  2. Isoprene formation
  3. Condensation to squalene (use of 6 isoprenoids)
  4. Ring closure (Squalene to Cholesterol)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe the stages in the first step of cholesterol biosynthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

List the steps in the first stage of cholesterol biosynthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Describe the biological regulation of cholesterol synthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Discuss the pharmacological regulation of cholesterol synthesis

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the fates of Cholesterol

A

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

17
Q

What are the hormones produced from cholesterol?

A

Progesterone
Cortisol
Testosterone
Estradiol

18
Q

Discuss the purpose of cholesterol being convert to Bile components

A
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