1.07 - Ketone Bodies & Cholesterol Flashcards
Describe the use of alternate fuels in various tissues
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
Discuss ketone bodies and the liver
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”
List the steps in the synthesis of Ketone Bodies
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)
Discuss the utilisation of ketone bodies as a fuel
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
List the steps in Ketone Body breakdown for use as a fuel
Beta-hydroxy-butyrate + NAD+ –> Acetoacetate + NADH
Aceto-acetate + Succinyl-CoA –> Aceto-Acetyl-CoA + Succinate
Aceto-Acetyl-CoA –> 2x Acetyl-CoA
Acetyl CoA –> TCA Cycle
Describe the association between ketone bodies and starvation
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
Describe the association between ketone bodies and untreated diabetes
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
What are the consequences of unregulated ketone body synthesis
Leads to accumulation acetoacetate and beta-hydroxy-butyrate –> plasma pH acidifies. This is known as ketosis.
Extreme ketosis can cause death.
What are the roles of Cholesterol
Membrane structure
Hormone composition
Fat emulsification
Describe cholesterol biosynthesis
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
What are the four main steps in cholesterol biosynthesis?
- Mevalonate synthesis from acetyl-CoA
- Isoprene formation
- Condensation to squalene (use of 6 isoprenoids)
- Ring closure (Squalene to Cholesterol)
Describe the stages in the first step of cholesterol biosynthesis
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
List the steps in the first stage of cholesterol biosynthesis
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
Describe the biological regulation of cholesterol synthesis
Biosynthesis is tightly regulated
Cellular [cholesterol] is the key factor
Enzyme = HMG-CoA reductase
•Amount and activity altered
Discuss the pharmacological regulation of cholesterol synthesis
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